Small Molecule Modulators of AMP-Activated Protein Kinase (AMPK) Activity and Their Potential in Cancer Therapy

Click to copy article linkArticle link copied!

This article references 122 other publications.

1. 1

   Carling, D. AMPK signalling in health and disease. Curr. Opin Cell Biol. 2017, 45, 31– 37,  DOI: 10.1016/j.ceb.2017.01.005

   Google Scholar

   1

   AMPK signalling in health and disease

   Carling, David

   Current Opinion in Cell Biology (2017), 45 (), 31-37CODEN: COCBE3; ISSN:0955-0674. (Elsevier Ltd.)

   A review. In eukaryotic cells AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance. AMPK responds to changes in intracellular adenine nucleotide levels, being activated by an increase in AMP/ADP relative to ATP. Activation of AMPK increases the rate of catabolic (ATP-generating) pathways and decreases the rate of anabolic (ATP-utilizing) pathways. In addn. to its role in maintaining intracellular energy balance, AMPK regulates whole body energy metab. Given its key role in controlling energy homeostasis, AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases, including type 2 diabetes and, more recently, cancer. Here I review the regulation of AMPK and its potential as a target for therapeutic intervention in human disease.
2. 2

   Steinberg, G. R.; Carling, D. AMP-activated protein kinase: the current landscape for drug development. Nat. Rev. Drug Discov 2019, 18 (7), 527– 551,  DOI: 10.1038/s41573-019-0019-2

   Google Scholar

   There is no corresponding record for this reference.
3. 3

   Hardie, D. G. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem. Soc. Trans. 2011, 39 (1), 1– 13,  DOI: 10.1042/BST0390001

   Google Scholar

   3

   AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer

   Hardie, D. Grahame

   Biochemical Society Transactions (2011), 39 (1), 1-13CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)

   A review. It is essential to life that a balance is maintained between processes that produce ATP and those that consume it. An obvious way to do this would be to have systems that monitor the levels of ATP and ADP, although because of the adenylate kinase reaction (2ADP ATP + AMP), AMP is actually a more sensitive indicator of energy stress than ADP. Following the discoveries that glycogen phosphorylase and phosphofructokinase were regulated by AMP and ATP, Daniel Atkinson proposed that all enzymes at branch points between biosynthesis and degrdn. would be regulated by adenine nucleotides. This turned out to be correct, but what Atkinson did not anticipate was that sensing of nucleotides would, in most cases, be performed not by the metabolic enzymes themselves, but by a signaling protein, AMPK (AMP-activated protein kinase). AMPK occurs in essentially all eukaryotes and consists of heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits, of which the latter carries the nucleotide-binding sites. Once activated by a metabolic stress, it phosphorylates numerous targets that alter enzyme activity and gene expression to initiate corrective responses. In lower eukaryotes, it is critically involved in the responses to starvation for a carbon source. Because of its ability to switch cellular metab. from anabolic to catabolic mode, AMPK has become a key drug target to combat metabolic disorders assocd. with overnutrition such as Type 2 diabetes, and some existing anti-diabetic drugs (e.g. metformin) and many nutraceuticals' work by activating AMPK, usually via inhibition of mitochondrial ATP prodn. AMPK activators also potentially have anticancer effects, and there is already evidence that metformin provides protection against the initiation of cancer. Whether AMPK activators can be used to treat existing cancer is less clear, because many tumor cells appear to have been selected for mutations that inactivate the AMPK system. However, if we can identify the various mechanisms by which this occurs, we may be able to find ways of overcoming it.
4. 4

   Steinberg, G. R.; Kemp, B. E. AMPK in Health and Disease. Physiol Rev. 2009, 89 (3), 1025– 1078,  DOI: 10.1152/physrev.00011.2008

   Google Scholar

   4

   AMPK in health and disease

   Steinberg, Gregory R.; Kemp, Bruce E.

   Physiological Reviews (2009), 89 (3), 1025-1078CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)

   A review. The function and survival of all organisms is dependent on the dynamic control of energy metab., when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochem. pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the mol. basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examn. of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.
5. 5

   Keerthana, C. K.; Rayginia, T. P.; Shifana, S. C.; Anto, N. P.; Kalimuthu, K.; Isakov, N.; Anto, R. J. The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment. Front Immunol 2023, 14, 1114582,  DOI: 10.3389/fimmu.2023.1114582

   Google Scholar

   There is no corresponding record for this reference.
6. 6

   Penugurti, V.; Mishra, Y. G.; Manavathi, B. AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene. Biochim Biophys Acta Rev. Cancer 2022, 1877 (5), 188785,  DOI: 10.1016/j.bbcan.2022.188785

   Google Scholar

   There is no corresponding record for this reference.
7. 7

   Dite, T. A.; Langendorf, C. G.; Hoque, A.; Galic, S.; Rebello, R. J.; Ovens, A. J.; Lindqvist, L. M.; Ngoei, K. R. W.; Ling, N. X. Y.; Furic, L. AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965. J. Biol. Chem. 2018, 293 (23), 8874– 8885,  DOI: 10.1074/jbc.RA118.003547

   Google Scholar

   There is no corresponding record for this reference.
8. 8

   Matheson, C. J.; Casalvieri, K. A.; Backos, D. S.; Minhajuddin, M.; Jordan, C. T.; Reigan, P. Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors. Eur. J. Med. Chem. 2020, 197, 112316,  DOI: 10.1016/j.ejmech.2020.112316

   Google Scholar

   8

   Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors

   Matheson, Christopher J.; Casalvieri, Kimberly A.; Backos, Donald S.; Minhajuddin, Mohammed; Jordan, Craig T.; Reigan, Philip

   European Journal of Medicinal Chemistry (2020), 197 (), 112316CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

   Design and synthesis of oxindoles I (R1 = H, F, CN, etc., R2 = H; R1 = H, R2 = F, Cl, Br, Me, Et, i-Pr; R3 = H, Me; R4 = OH, n-PrNH, Me2NCH2CH2NH, EtNHCH2CH2NH, Et2NCH2CH2NH, etc.) is reported to det. the structural requirements for AMP-activated protein kinase (AMPK) inhibition and to improve selectivity. Two potent, novel oxindole-based AMPK inhibitors I (R1 = HOCH2CH2, H2NCOCH2CH2; R2 = R3 = H; R4 = Et2NCH2CH2NH) have been identified that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common receptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells, these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. These studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.
9. 9

   Lemos, C.; Schulze, V. K.; Baumgart, S. J.; Nevedomskaya, E.; Heinrich, T.; Lefranc, J.; Bader, B.; Christ, C. D.; Briem, H.; Kuhnke, L. P. The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models. Cell Oncol (Dordr) 2021, 44 (3), 581– 594,  DOI: 10.1007/s13402-020-00584-8

   Google Scholar

   There is no corresponding record for this reference.
10. 10

    Xiao, B.; Sanders, M. J.; Carmena, D.; Bright, N. J.; Haire, L. F.; Underwood, E.; Patel, B. R.; Heath, R. B.; Walker, P. A.; Hallen, S. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 2013, 4, 3017,  DOI: 10.1038/ncomms4017

    Google Scholar

    10

    Structural basis of AMPK regulation by small molecule activators

    Xiao Bing; Sanders Matthew J; Heath Richard B; Carmena David; Bright Nicola J; Patel Bhakti R; Carling David; Haire Lesley F; Underwood Elizabeth; Walker Philip A; Martin Stephen R; Gamblin Steven J; Hallen Stefan; Giordanetto Fabrizio

    Nature communications (2013), 4 (), 3017 ISSN:.

    AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders.
11. 11

    Ross, F. A.; MacKintosh, C.; Hardie, D. G. AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours. FEBS J. 2016, 283 (16), 2987– 3001,  DOI: 10.1111/febs.13698

    Google Scholar

    There is no corresponding record for this reference.
12. 12

    Stapleton, D.; Mitchelhill, K. I.; Gao, G.; Widmer, J.; Michell, B. J.; Teh, T.; House, C. M.; Fernandez, C. S.; Cox, T.; Witters, L. A. Mammalian AMP-activated protein kinase subfamily. J. Biol. Chem. 1996, 271 (2), 611– 614,  DOI: 10.1074/jbc.271.2.611

    Google Scholar

    There is no corresponding record for this reference.
13. 13

    Rajamohan, F.; Reyes, A. R.; Frisbie, R. K.; Hoth, L. R.; Sahasrabudhe, P.; Magyar, R.; Landro, J. A.; Withka, J. M.; Caspers, N. L.; Calabrese, M. F. Probing the enzyme kinetics, allosteric modulation and activation of alpha1- and alpha2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. Biochem. J. 2016, 473 (5), 581– 592,  DOI: 10.1042/BJ20151051

    Google Scholar

    There is no corresponding record for this reference.
14. 14

    Yan, Y.; Zhou, X. E.; Xu, H. E.; Melcher, K. Structure and Physiological Regulation of AMPK. Int. J. Mol. Sci. 2018, 19 (11), 3534,  DOI: 10.3390/ijms19113534

    Google Scholar

    There is no corresponding record for this reference.
15. 15

    Gu, X.; Yan, Y.; Novick, S. J.; Kovach, A.; Goswami, D.; Ke, J.; Tan, M. H. E.; Wang, L.; Li, X.; de Waal, P. W. Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing. J. Biol. Chem. 2017, 292 (30), 12653– 12666,  DOI: 10.1074/jbc.M117.793018

    Google Scholar

    There is no corresponding record for this reference.
16. 16

    Steinberg, G. R.; Hardie, D. G. New insights into activation and function of the AMPK. Nat. Rev. Mol. Cell Biol. 2023, 24 (4), 255– 272,  DOI: 10.1038/s41580-022-00547-x

    Google Scholar

    There is no corresponding record for this reference.
17. 17

    Jeon, S. M. Regulation and function of AMPK in physiology and diseases. Exp Mol. Med. 2016, 48 (7), e245  DOI: 10.1038/emm.2016.81

    Google Scholar

    17

    Regulation and function of AMPK in physiology and diseases

    Jeon, Sang-Min

    Experimental & Molecular Medicine (2016), 48 (7), e245CODEN: EMMEF3; ISSN:2092-6413. (NPG Nature Asia-Pacific)

    5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that was originally identified as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has identified diverse mol. mechanisms and physiol. conditions that regulate the AMPK activity. AMPK regulates diverse metabolic and physiol. processes and is dysregulated in major chronic diseases, such as obesity, inflammation, diabetes and cancer. On the basis of its crit. roles in physiol. and pathol., AMPK is emerging as one of the most promising targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the mol. and physiol. regulation of AMPK and its metabolic and physiol. functions. In addn., we discuss the mechanisms underlying the versatile roles of AMPK in diabetes and cancer.
18. 18

    Viollet, B.; Horman, S.; Leclerc, J.; Lantier, L.; Foretz, M.; Billaud, M.; Giri, S.; Andreelli, F. AMPK inhibition in health and disease. Crit Rev. Biochem Mol. Biol. 2010, 45 (4), 276– 295,  DOI: 10.3109/10409238.2010.488215

    Google Scholar

    There is no corresponding record for this reference.
19. 19

    Hardie, D. G.; Pan, D. A. Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase. Biochem. Soc. Trans. 2002, 30 (Pt 6), 1064– 1070,  DOI: 10.1042/bst0301064

    Google Scholar

    There is no corresponding record for this reference.
20. 20

    Barnes, K.; Ingram, J. C.; Porras, O. H.; Barros, L. F.; Hudson, E. R.; Fryer, L. G.; Foufelle, F.; Carling, D.; Hardie, D. G.; Baldwin, S. A. Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J. Cell Sci. 2002, 115 (Pt 11), 2433– 2442,  DOI: 10.1242/jcs.115.11.2433

    Google Scholar

    There is no corresponding record for this reference.
21. 21

    Almeida, A.; Moncada, S.; Bolanos, J. P. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat. Cell Biol. 2004, 6 (1), 45– 51,  DOI: 10.1038/ncb1080

    Google Scholar

    There is no corresponding record for this reference.
22. 22

    Jager, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (29), 12017– 12022,  DOI: 10.1073/pnas.0705070104

    Google Scholar

    There is no corresponding record for this reference.
23. 23

    Guo, D.; Cloughesy, T. F.; Radu, C. G.; Mischel, P. S. AMPK: A metabolic checkpoint that regulates the growth of EGFR activated glioblastomas. Cell Cycle 2010, 9 (2), 211– 212,  DOI: 10.4161/cc.9.2.10540

    Google Scholar

    There is no corresponding record for this reference.
24. 24

    Garcia, D.; Shaw, R. J. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol. Cell 2017, 66 (6), 789– 800,  DOI: 10.1016/j.molcel.2017.05.032

    Google Scholar

    24

    AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

    Garcia, Daniel; Shaw, Reuben J.

    Molecular Cell (2017), 66 (6), 789-800CODEN: MOCEFL; ISSN:1097-2765. (Elsevier Inc.)

    AMPK is a highly conserved master regulator of metab., which restores energy balance during metabolic stress both at the cellular and physiol. levels. The identification of numerous AMPK targets has helped explain how AMPK restores energy homeostasis. Recent advancements illustrate novel mechanisms of AMPK regulation, including changes in subcellular localization and phosphorylation by non-canonical upstream kinases. Notably, the therapeutic potential of AMPK is widely recognized and heavily pursued for treatment of metabolic diseases such as diabetes, but also obesity, inflammation, and cancer. Moreover, the recently solved crystal structure of AMPK has shed light both into how nucleotides activate AMPK and, importantly, also into the sites bound by small mol. activators, thus providing a path for improved drugs.
25. 25

    Hoffman, N. J.; Parker, B. L.; Chaudhuri, R.; Fisher-Wellman, K. H.; Kleinert, M.; Humphrey, S. J.; Yang, P.; Holliday, M.; Trefely, S.; Fazakerley, D. J. Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates. Cell Metab 2015, 22 (5), 922– 935,  DOI: 10.1016/j.cmet.2015.09.001

    Google Scholar

    25

    Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates

    Hoffman, Nolan J.; Parker, Benjamin L.; Chaudhuri, Rima; Fisher-Wellman, Kelsey H.; Kleinert, Maximilian; Humphrey, Sean J.; Yang, Pengyi; Holliday, Mira; Trefely, Sophie; Fazakerley, Daniel J.; Stockli, Jacqueline; Burchfield, James G.; Jensen, Thomas E.; Jothi, Raja; Kiens, Bente; Wojtaszewski, Joergen F. P.; Richter, Erik A.; James, David E.

    Cell Metabolism (2015), 22 (5), 922-935CODEN: CMEEB5; ISSN:1550-4131. (Elsevier Inc.)

    Exercise is essential in regulating energy metab. and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global anal. of protein phosphorylation in human skeletal muscle biopsies from untrained healthy males before and after a single high-intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases (AMPK, PKA, CaMK, MAPK, mTOR), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given the importance of AMPK in exercise-regulated metab., we performed a targeted in vitro AMPK screen and employed machine learning to predict exercise-regulated AMPK substrates. We validated eight predicted AMPK substrates, including AKAP1, using targeted phosphoproteomics. Functional characterization revealed an undescribed role for AMPK-dependent phosphorylation of AKAP1 in mitochondrial respiration. These data expose the unexplored complexity of acute exercise signaling and provide insights into the role of AMPK in mitochondrial biochem.
26. 26

    Toyama, E. Q.; Herzig, S.; Courchet, J.; Lewis, T. L., Jr; Loson, O. C.; Hellberg, K.; Young, N. P.; Chen, H.; Polleux, F.; Chan, D. C. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 2016, 351 (6270), 275– 281,  DOI: 10.1126/science.aab4138

    Google Scholar

    There is no corresponding record for this reference.
27. 27

    Egan, D. F.; Shackelford, D. B.; Mihaylova, M. M.; Gelino, S.; Kohnz, R. A.; Mair, W.; Vasquez, D. S.; Joshi, A.; Gwinn, D. M.; Taylor, R. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 2011, 331 (6016), 456– 461,  DOI: 10.1126/science.1196371

    Google Scholar

    27

    Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy

    Egan, Daniel F.; Shackelford, David B.; Mihaylova, Maria M.; Gelino, Sara; Kohnz, Rebecca A.; Mair, William; Vasquez, Debbie S.; Joshi, Aashish; Gwinn, Dana M.; Taylor, Rebecca; Asara, John M.; Fitzpatrick, James; Dillin, Andrew; Viollet, Benoit; Kundu, Mondira; Hansen, Malene; Shaw, Reuben J.

    Science (Washington, DC, United States) (2011), 331 (6016), 456-461CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

    Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic anal. of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochem. mechanism coupling nutrient status with autophagy and cell survival.
28. 28

    Clarke, P. R.; Hardie, D. G. Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J. 1990, 9 (8), 2439– 2446,  DOI: 10.1002/j.1460-2075.1990.tb07420.x

    Google Scholar

    There is no corresponding record for this reference.
29. 29

    Chavez, J. A.; Roach, W. G.; Keller, S. R.; Lane, W. S.; Lienhard, G. E. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. J. Biol. Chem. 2008, 283 (14), 9187– 9195,  DOI: 10.1074/jbc.M708934200

    Google Scholar

    There is no corresponding record for this reference.
30. 30

    Bando, H.; Atsumi, T.; Nishio, T.; Niwa, H.; Mishima, S.; Shimizu, C.; Yoshioka, N.; Bucala, R.; Koike, T. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Clin. Cancer Res. 2005, 11 (16), 5784– 5792,  DOI: 10.1158/1078-0432.CCR-05-0149

    Google Scholar

    There is no corresponding record for this reference.
31. 31

    Johanns, M.; Pyr Dit Ruys, S.; Houddane, A.; Vertommen, D.; Herinckx, G.; Hue, L.; Proud, C. G.; Rider, M. H. Direct and indirect activation of eukaryotic elongation factor 2 kinase by AMP-activated protein kinase. Cell Signal 2017, 36, 212– 221,  DOI: 10.1016/j.cellsig.2017.05.010

    Google Scholar

    There is no corresponding record for this reference.
32. 32

    Gwinn, D. M.; Shackelford, D. B.; Egan, D. F.; Mihaylova, M. M.; Mery, A.; Vasquez, D. S.; Turk, B. E.; Shaw, R. J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 2008, 30 (2), 214– 226,  DOI: 10.1016/j.molcel.2008.03.003

    Google Scholar

    There is no corresponding record for this reference.
33. 33

    Inoki, K.; Zhu, T.; Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115 (5), 577– 590,  DOI: 10.1016/S0092-8674(03)00929-2

    Google Scholar

    33

    TSC2 mediates cellular energy response to control cell growth and survival

    Inoki, Ken; Zhu, Tianqing; Guan, Kun-liang

    Cell (Cambridge, MA, United States) (2003), 115 (5), 577-590CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for Tuberous Sclerosis Complex. The gene products of TSC1 and TSC2 form a functional complex and inhibit the phosphorylation of S6K and 4EBP1, two key regulators of translation. Here, we describe that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway. Under energy starvation conditions, the AMP-activated protein kinase (AMPK) phosphorylates TSC2 and enhances its activity. Phosphorylation of TSC2 by AMPK is required for translation regulation and cell size control in response to energy deprivation. Furthermore, TSC2 and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis. These observations demonstrate a model where TSC2 functions as a key player in regulation of the common mTOR pathway of protein synthesis, cell growth, and viability in response to cellular energy levels.
34. 34

    Jones, R. G.; Plas, D. R.; Kubek, S.; Buzzai, M.; Mu, J.; Xu, Y.; Birnbaum, M. J.; Thompson, C. B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 2005, 18 (3), 283– 293,  DOI: 10.1016/j.molcel.2005.03.027

    Google Scholar

    There is no corresponding record for this reference.
35. 35

    Liang, J.; Shao, S. H.; Xu, Z. X.; Hennessy, B.; Ding, Z.; Larrea, M.; Kondo, S.; Dumont, D. J.; Gutterman, J. U.; Walker, C. L. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat. Cell Biol. 2007, 9 (2), 218– 224,  DOI: 10.1038/ncb1537

    Google Scholar

    There is no corresponding record for this reference.
36. 36

    Banko, M. R.; Allen, J. J.; Schaffer, B. E.; Wilker, E. W.; Tsou, P.; White, J. L.; Villen, J.; Wang, B.; Kim, S. R.; Sakamoto, K. Chemical genetic screen for AMPKalpha2 substrates uncovers a network of proteins involved in mitosis. Mol. Cell 2011, 44 (6), 878– 892,  DOI: 10.1016/j.molcel.2011.11.005

    Google Scholar

    There is no corresponding record for this reference.
37. 37

    Vara-Ciruelos, D.; Dandapani, M.; Hardie, D. G. AMP-Activated Protein Kinase: Friend or Foe in Cancer?. Annual Review of Cancer Biology 2020, 4 (1), 1– 16,  DOI: 10.1146/annurev-cancerbio-030419-033619

    Google Scholar

    There is no corresponding record for this reference.
38. 38

    Rehman, G.; Shehzad, A.; Khan, A. L.; Hamayun, M. Role of AMP-activated protein kinase in cancer therapy. Arch Pharm. (Weinheim) 2014, 347 (7), 457– 468,  DOI: 10.1002/ardp.201300402

    Google Scholar

    There is no corresponding record for this reference.
39. 39

    Zadra, G.; Batista, J. L.; Loda, M. Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies. Mol. Cancer Res. 2015, 13 (7), 1059– 1072,  DOI: 10.1158/1541-7786.MCR-15-0068

    Google Scholar

    There is no corresponding record for this reference.
40. 40

    Russell, F. M.; Hardie, D. G. AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?. Int. J. Mol. Sci. 2021, 22 (1), 186,  DOI: 10.3390/ijms22010186

    Google Scholar

    There is no corresponding record for this reference.
41. 41

    Dasgupta, B.; Chhipa, R. R. Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer. Trends Pharmacol. Sci. 2016, 37 (3), 192– 206,  DOI: 10.1016/j.tips.2015.11.007

    Google Scholar

    There is no corresponding record for this reference.
42. 42

    Vara-Ciruelos, D.; Russell, F. M.; Hardie, D. G. The strange case of AMPK and cancer: Dr Jekyll or Mr Hyde? (dagger). Open Biol. 2019, 9 (7), 190099,  DOI: 10.1098/rsob.190099

    Google Scholar

    There is no corresponding record for this reference.
43. 43

    Hardie, D. G.; Alessi, D. R. LKB1 and AMPK and the cancer-metabolism link - ten years after. BMC Biol. 2013, 11, 36,  DOI: 10.1186/1741-7007-11-36

    Google Scholar

    43

    LKB1 and AMPK and the cancer-metabolism link - ten years after

    Hardie D Grahame; Alessi Dario R

    BMC biology (2013), 11 (), 36 ISSN:.

    The identification of a complex containing the tumor suppressor LKB1 as the critical upstream kinase required for the activation of AMP-activated protein kinase (AMPK) by metabolic stress was reported in an article in Journal of Biology in 2003. This finding represented the first clear link between AMPK and cancer. Here we briefly discuss how this discovery came about, and describe some of the insights, especially into the role of AMPK in cancer, that have followed from it.
44. 44

    Dai, X.; Bu, X.; Gao, Y.; Guo, J.; Hu, J.; Jiang, C.; Zhang, Z.; Xu, K.; Duan, J.; He, S. Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol. Cell 2021, 81 (11), 2317– 2331,  DOI: 10.1016/j.molcel.2021.03.037

    Google Scholar

    There is no corresponding record for this reference.
45. 45

    Faubert, B.; Boily, G.; Izreig, S.; Griss, T.; Samborska, B.; Dong, Z.; Dupuy, F.; Chambers, C.; Fuerth, B. J.; Viollet, B. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 2013, 17 (1), 113– 124,  DOI: 10.1016/j.cmet.2012.12.001

    Google Scholar

    There is no corresponding record for this reference.
46. 46

    Houde, V. P.; Donzelli, S.; Sacconi, A.; Galic, S.; Hammill, J. A.; Bramson, J. L.; Foster, R. A.; Tsakiridis, T.; Kemp, B. E.; Grasso, G. AMPK beta1 reduces tumor progression and improves survival in p53 null mice. Mol. Oncol 2017, 11 (9), 1143– 1155,  DOI: 10.1002/1878-0261.12079

    Google Scholar

    There is no corresponding record for this reference.
47. 47

    Penfold, L.; Woods, A.; Muckett, P.; Nikitin, A. Y.; Kent, T. R.; Zhang, S.; Graham, R.; Pollard, A.; Carling, D. CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis. Cancer Res. 2018, 78 (24), 6747– 6761,  DOI: 10.1158/0008-5472.CAN-18-0585

    Google Scholar

    There is no corresponding record for this reference.
48. 48

    Rolf, J.; Zarrouk, M.; Finlay, D. K.; Foretz, M.; Viollet, B.; Cantrell, D. A. AMPKalpha1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. 2013, 43 (4), 889– 896,  DOI: 10.1002/eji.201243008

    Google Scholar

    There is no corresponding record for this reference.
49. 49

    Vara-Ciruelos, D.; Dandapani, M.; Russell, F. M.; Grzes, K. M.; Atrih, A.; Foretz, M.; Viollet, B.; Lamont, D. J.; Cantrell, D. A.; Hardie, D. G. Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation. Cell Rep 2019, 27 (3), 690– 698,  DOI: 10.1016/j.celrep.2019.03.067

    Google Scholar

    There is no corresponding record for this reference.
50. 50

    Liberti, M. V.; Locasale, J. W. The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem. Sci. 2016, 41 (3), 211– 218,  DOI: 10.1016/j.tibs.2015.12.001

    Google Scholar

    50

    The Warburg Effect: How Does it Benefit Cancer Cells?

    Liberti, Maria V.; Locasale, Jason W.

    Trends in Biochemical Sciences (2016), 41 (3), 211-218CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)

    Cancer cells rewire their metab. to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metab. is the increased glucose uptake and fermn. of glucose to lactate. This phenomenon is obsd. even in the presence of completely functioning mitochondria and, together, is known as the 'Warburg Effect'. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. Despite this intense interest, the function of the Warburg Effect remains unclear. Here, we analyze several proposed explanations for the function of Warburg Effect, emphasize their rationale, and discuss their controversies.
51. 51

    Jeon, S. M.; Chandel, N. S.; Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 2012, 485 (7400), 661– 665,  DOI: 10.1038/nature11066

    Google Scholar

    There is no corresponding record for this reference.
52. 52

    Liang, J.; Mills, G. B. AMPK: a contextual oncogene or tumor suppressor?. Cancer Res. 2013, 73 (10), 2929– 2935,  DOI: 10.1158/0008-5472.CAN-12-3876

    Google Scholar

    There is no corresponding record for this reference.
53. 53

    Shaw, R. J. AMPK Keeps Tumor Cells from Starving to Death. Cell Stem Cell 2015, 17 (5), 503– 504,  DOI: 10.1016/j.stem.2015.10.007

    Google Scholar

    There is no corresponding record for this reference.
54. 54

    Rios, M.; Foretz, M.; Viollet, B.; Prieto, A.; Fraga, M.; Costoya, J. A.; Senaris, R. AMPK activation by oncogenesis is required to maintain cancer cell proliferation in astrocytic tumors. Cancer Res. 2013, 73 (8), 2628– 2638,  DOI: 10.1158/0008-5472.CAN-12-0861

    Google Scholar

    There is no corresponding record for this reference.
55. 55

    Li, W.; Saud, S. M.; Young, M. R.; Chen, G.; Hua, B. Targeting AMPK for cancer prevention and treatment. Oncotarget 2015, 6 (10), 7365– 7378,  DOI: 10.18632/oncotarget.3629

    Google Scholar

    There is no corresponding record for this reference.
56. 56

    Castedo, M.; Perfettini, J. L.; Roumier, T.; Andreau, K.; Medema, R.; Kroemer, G. Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004, 23 (16), 2825– 2837,  DOI: 10.1038/sj.onc.1207528

    Google Scholar

    56

    Cell death by mitotic catastrophe: a molecular definition

    Castedo, Maria; Perfettini, Jean-Luc; Roumier, Thomas; Andreau, Karine; Medema, Rene; Kroemer, Guido

    Oncogene (2004), 23 (16), 2825-2837CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)

    A review. The current literature is devoid of a clearcut definition of mitotic catastrophe, a type of cell death that occurs during mitosis. Here, we propose that mitotic catastrophe results from a combination of deficient cell-cycle checkpoints (in particular the DNA structure checkpoints and the spindle assembly checkpoint) and cellular damage. Failure to arrest the cell cycle before or at mitosis triggers an attempt of aberrant chromosome segregation, which culminates in the activation of the apoptotic default pathway and cellular demise. Cell death occurring during the metaphase/anaphase transition is characterized by the activation of caspase-2 (which can be activated in response to DNA damage) and/or mitochondrial membrane permeabilization with the release of cell death effectors such as apoptosis-inducing factor and the caspase-9 and-3 activator cytochrome c. Although the morphol. aspect of apoptosis may be incomplete, these alterations constitute the biochem. hallmarks of apoptosis. Cells that fail to execute an apoptotic program in response to mitotic failure are likely to divide asym. in the next round of cell division, with the consequent generation of aneuploid cells. This implies that disabling of the apoptotic program may actually favor chromosomal instability, through the suppression of mitotic catastrophe. Mitotic catastrophe thus may be conceived as a mol. device that prevents aneuploidization, which may participate in oncogenesis. Mitotic catastrophe is controlled by numerous mol. players, in particular, cell-cycle-specific kinases (such as the cyclin B1-dependent kinase Cdk1, polo-like kinases and Aurora kinases), cell-cycle checkpoint proteins, survivin, p53, caspases and members of the Bcl-2 family.
57. 57

    Emerling, B. M.; Weinberg, F.; Snyder, C.; Burgess, Z.; Mutlu, G. M.; Viollet, B.; Budinger, G. R.; Chandel, N. S. Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radic Biol. Med. 2009, 46 (10), 1386– 1391,  DOI: 10.1016/j.freeradbiomed.2009.02.019

    Google Scholar

    There is no corresponding record for this reference.
58. 58

    Wu, N.; Zheng, B.; Shaywitz, A.; Dagon, Y.; Tower, C.; Bellinger, G.; Shen, C. H.; Wen, J.; Asara, J.; McGraw, T. E. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 2013, 49 (6), 1167– 1175,  DOI: 10.1016/j.molcel.2013.01.035

    Google Scholar

    There is no corresponding record for this reference.
59. 59

    Vincent, E. E.; Coelho, P. P.; Blagih, J.; Griss, T.; Viollet, B.; Jones, R. G. Differential effects of AMPK agonists on cell growth and metabolism. Oncogene 2015, 34 (28), 3627– 3639,  DOI: 10.1038/onc.2014.301

    Google Scholar

    There is no corresponding record for this reference.
60. 60

    Chhipa, R. R.; Fan, Q.; Anderson, J.; Muraleedharan, R.; Huang, Y.; Ciraolo, G.; Chen, X.; Waclaw, R.; Chow, L. M.; Khuchua, Z. AMP kinase promotes glioblastoma bioenergetics and tumour growth. Nat. Cell Biol. 2018, 20 (7), 823– 835,  DOI: 10.1038/s41556-018-0126-z

    Google Scholar

    There is no corresponding record for this reference.
61. 61

    Saito, Y.; Chapple, R. H.; Lin, A.; Kitano, A.; Nakada, D. AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow. Cell Stem Cell 2015, 17 (5), 585– 596,  DOI: 10.1016/j.stem.2015.08.019

    Google Scholar

    There is no corresponding record for this reference.
62. 62

    Kreso, A.; Dick, J. E. Evolution of the cancer stem cell model. Cell Stem Cell 2014, 14 (3), 275– 291,  DOI: 10.1016/j.stem.2014.02.006

    Google Scholar

    62

    Evolution of the Cancer Stem Cell Model

    Kreso, Antonija; Dick, John E.

    Cell Stem Cell (2014), 14 (3), 275-291CODEN: CSCEC4; ISSN:1875-9777. (Elsevier Inc.)

    A review. Genetic analyses have shaped much of our understanding of cancer. However, it is becoming increasingly clear that cancer cells display features of normal tissue organization, where cancer stem cells (CSCs) can drive tumor growth. Although often considered as mutually exclusive models to describe tumor heterogeneity, we propose that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity. The authors offer an approach to integrating CSCs and cancer genetic data that will guide the field in interpreting past observations and designing future studies.
63. 63

    Lagadinou, E. D.; Sach, A.; Callahan, K.; Rossi, R. M.; Neering, S. J.; Minhajuddin, M.; Ashton, J. M.; Pei, S.; Grose, V.; O’Dwyer, K. M. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 2013, 12 (3), 329– 341,  DOI: 10.1016/j.stem.2012.12.013

    Google Scholar

    63

    BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells

    Lagadinou, Eleni D.; Sach, Alexander; Callahan, Kevin; Rossi, Randall M.; Neering, Sarah J.; Minhajuddin, Mohammad; Ashton, John M.; Pei, Shanshan; Grose, Valerie; O'Dwyer, Kristen M.; Liesveld, Jane L.; Brookes, Paul S.; Becker, Michael W.; Jordan, Craig T.

    Cell Stem Cell (2013), 12 (3), 329-341CODEN: CSCEC4; ISSN:1875-9777. (Elsevier Inc.)

    Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly obsd. in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematol. malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed "ROS-low"). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiol. of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
64. 64

    Guieze, R.; Liu, V. M.; Rosebrock, D.; Jourdain, A. A.; Hernandez-Sanchez, M.; Martinez Zurita, A.; Sun, J.; Ten Hacken, E.; Baranowski, K.; Thompson, P. A. Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies. Cancer Cell 2019, 36 (4), 369– 384,  DOI: 10.1016/j.ccell.2019.08.005

    Google Scholar

    There is no corresponding record for this reference.
65. 65

    Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin Invest 2001, 108 (8), 1167– 1174,  DOI: 10.1172/JCI13505

    Google Scholar

    65

    Role of AMP-activated protein kinase in mechanism of metformin action

    Zhou, Gaochao; Myers, Robert; Li, Ying; Chen, Yuli; Shen, Xiaolan; Fenyk-Melody, Judy; Wu, Margaret; Ventre, John; Doebber, Thomas; Fujii, Nobuharu; Musi, Nicolas; Hirshman, Michael F.; Goodyear, Laurie J.; Moller, David E.

    Journal of Clinical Investigation (2001), 108 (8), 1167-1174CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)

    Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose prodn. and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metab. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidn. is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analog suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose prodn. by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.
66. 66

    El-Mir, M. Y.; Nogueira, V.; Fontaine, E.; Averet, N.; Rigoulet, M.; Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 2000, 275 (1), 223– 228,  DOI: 10.1074/jbc.275.1.223

    Google Scholar

    66

    Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I

    El-Mir, Mohamad-Yehia; Nogueira, Veronique; Fontaine, Eric; Averet, Nicole; Rigoulet, Michel; Leverve, Xavier

    Journal of Biological Chemistry (2000), 275 (1), 223-228CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    The authors report here a new mitochondrial regulation occurring only in intact cells. The authors have investigated the effects of dimethylbiguanide on isolated rat hepatocytes, permeabilized hepatocytes, and isolated liver mitochondria. Addn. of dimethylbiguanide decreased oxygen consumption and mitochondrial membrane potential only in intact cells but not in permeabilized hepatocytes or isolated mitochondria. Permeabilized hepatocytes after dimethylbiguanide exposure and mitochondria isolated from dimethylbiguanide pretreated livers or animals were characterized by a significant inhibition of oxygen consumption with complex I substrates (glutamate and malate) but not with complex II (succinate) or complex IV (N,N,N',N'-tetramethyl-1,4-phenylenediamine dihydrochloride (TMPD)/ascorbate) substrates. Studies using functionally isolated complex I obtained from mitochondria isolated from dimethylbiguanide-pretreated livers or rats further confirmed that dimethylbiguanide action was located on the respiratory chain complex I. The dimethylbiguanide effect was temp.-dependent, oxygen consumption decreasing by 50, 20, and 0% at 37, 25, and 15°, resp. This effect was not affected by insulin-signaling pathway inhibitors, nitric oxide precursor or inhibitors, oxygen radical scavengers, ceramide synthesis inhibitors, or chelation of intra- or extracellular Ca2+. Because it is established that dimethylbiguanide is not metabolized, these results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.
67. 67

    Choi, J.; Lee, J. H.; Koh, I.; Shim, J. K.; Park, J.; Jeon, J. Y.; Yun, M.; Kim, S. H.; Yook, J. I.; Kim, E. H. Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with Temozolomide and a newly designed biguanide (HL156A). Oncotarget 2016, 7 (40), 65643– 65659,  DOI: 10.18632/oncotarget.11595

    Google Scholar

    There is no corresponding record for this reference.
68. 68

    Kuramoto, K.; Yamada, H.; Shin, T.; Sawada, Y.; Azami, H.; Yamada, T.; Nagashima, T.; Ohnuki, K. Development of a potent and orally active activator of adenosine monophosphate-activated protein kinase (AMPK), ASP4132, as a clinical candidate for the treatment of human cancer. Bioorg. Med. Chem. 2020, 28 (5), 115307,  DOI: 10.1016/j.bmc.2020.115307

    Google Scholar

    There is no corresponding record for this reference.
69. 69

    Janku, F.; LoRusso, P.; Mansfield, A. S.; Nanda, R.; Spira, A.; Wang, T.; Melhem-Bertrandt, A.; Sugg, J.; Ball, H. A. First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer. Invest New Drugs 2021, 39 (5), 1348– 1356,  DOI: 10.1007/s10637-021-01112-7

    Google Scholar

    There is no corresponding record for this reference.
70. 70

    Kuramoto, K.; Sawada, Y.; Yamada, T.; Nagashima, T.; Ohnuki, K.; Shin, T. Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity. Chem. Pharm. Bull. (Tokyo) 2020, 68 (5), 452– 465,  DOI: 10.1248/cpb.c20-00015

    Google Scholar

    There is no corresponding record for this reference.
71. 71

    Corton, J. M.; Gillespie, J. G.; Hawley, S. A.; Hardie, D. G. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?. Eur. J. Biochem. 1995, 229 (2), 558– 565,  DOI: 10.1111/j.1432-1033.1995.tb20498.x

    Google Scholar

    71

    5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?

    Corton, Julia M.; Gillespie, John G.; Hawley, Simon A.; Hardie, D. Grahame

    European Journal of Biochemistry (1995), 229 (2), 558-65CODEN: EJBCAI; ISSN:0014-2956. (Springer)

    The AMP-activated protein kinase (AMPK) is believed to protect cells against environmental stress (e.g. heat shock) by switching off biosynthetic pathways, the key signal being elevation of AMP. Identification of novel targets for the kinase cascade would be facilitated by development of a specific agent for activating the kinase in intact cells. Incubation of rat hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) results in accumulation of the monophosphorylated deriv. (5-aminoimidazole-4-carboxamide ribonucleoside monophosphate; ZMP) within the cell. ZMP mimics both activating effects of AMP on AMPK, i.e. direct allosteric activation and promotion of phosphorylation by AMPK kinase. Unlike existing methods for activating AMPK in intact cells (e.g. fructose, heat shock), AICAR does not perturb the cellular contents of ATP, ADP or AMP. Incubation of hepatocytes with AICAR activates AMPK due to increased phosphorylation, causes phosphorylation and inactivation of a known target for AMPK (3-hydroxy-3-methylglutaryl-CoA reductase), and almost total cessation of two of the known target pathways, i.e. fatty acid and sterol synthesis. Incubation of isolated adipocytes with AICAR antagonizes isoprenaline-induced lipolysis. This provides direct evidence that the inhibition by AMPK of activation of hormone-sensitive lipase by cyclic-AMP-dependent protein kinase, previously demonstrated in cell-free assays, also operates in intact cells. AICAR should be a useful tool for identifying new target pathways and processes regulated by the protein kinase cascade.
72. 72

    Day, P.; Sharff, A.; Parra, L.; Cleasby, A.; Williams, M.; Horer, S.; Nar, H.; Redemann, N.; Tickle, I.; Yon, J. Structure of a CBS-domain pair from the regulatory gamma1 subunit of human AMPK in complex with AMP and ZMP. Acta Crystallogr. D Biol. Crystallogr. 2007, 63 (Pt 5), 587– 596,  DOI: 10.1107/S0907444907009110

    Google Scholar

    There is no corresponding record for this reference.
73. 73

    Hunter, R. W.; Foretz, M.; Bultot, L.; Fullerton, M. D.; Deak, M.; Ross, F. A.; Hawley, S. A.; Shpiro, N.; Viollet, B.; Barron, D. Mechanism of action of compound-13: an alpha1-selective small molecule activator of AMPK. Chem. Biol. 2014, 21 (7), 866– 879,  DOI: 10.1016/j.chembiol.2014.05.014

    Google Scholar

    There is no corresponding record for this reference.
74. 74

    Beckers, A.; Organe, S.; Timmermans, L.; Vanderhoydonc, F.; Deboel, L.; Derua, R.; Waelkens, E.; Brusselmans, K.; Verhoeven, G.; Swinnen, J. V. Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside. Mol. Cancer Ther 2006, 5 (9), 2211– 2217,  DOI: 10.1158/1535-7163.MCT-06-0001

    Google Scholar

    There is no corresponding record for this reference.
75. 75

    Gomez-Galeno, J. E.; Dang, Q.; Nguyen, T. H.; Boyer, S. H.; Grote, M. P.; Sun, Z.; Chen, M.; Craigo, W. A.; van Poelje, P. D.; MacKenna, D. A. A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis. ACS Med. Chem. Lett. 2010, 1 (9), 478– 482,  DOI: 10.1021/ml100143q

    Google Scholar

    There is no corresponding record for this reference.
76. 76

    Langendorf, C. G.; Ngoei, K. R. W.; Scott, J. W.; Ling, N. X. Y.; Issa, S. M. A.; Gorman, M. A.; Parker, M. W.; Sakamoto, K.; Oakhill, J. S.; Kemp, B. E. Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nat. Commun. 2016, 7 (1), 10912,  DOI: 10.1038/ncomms10912

    Google Scholar

    There is no corresponding record for this reference.
77. 77

    Ge, W.; Zhang, W.; Gao, R.; Li, B.; Zhu, H.; Wang, J. IMM-H007 improves heart function via reducing cardiac fibrosis. Eur. J. Pharmacol. 2019, 857, 172442,  DOI: 10.1016/j.ejphar.2019.172442

    Google Scholar

    There is no corresponding record for this reference.
78. 78

    Bung, N.; Surepalli, S.; Seshadri, S.; Patel, S.; Peddasomayajula, S.; Kummari, L. K.; Kumar, S. T.; Babu, P. P.; Parsa, K. V. L.; Poondra, R. R. 2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid (Activator-3) is a potent activator of AMPK. Sci. Rep. 2018, 8 (1), 9599,  DOI: 10.1038/s41598-018-27974-1

    Google Scholar

    There is no corresponding record for this reference.
79. 79

    Steneberg, P.; Lindahl, E.; Dahl, U.; Lidh, E.; Straseviciene, J.; Backlund, F.; Kjellkvist, E.; Berggren, E.; Lundberg, I.; Bergqvist, I. PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI Insight 2018, 3 (12), e99114,  DOI: 10.1172/jci.insight.99114

    Google Scholar

    There is no corresponding record for this reference.
80. 80

    Jensen, T. E.; Ross, F. A.; Kleinert, M.; Sylow, L.; Knudsen, J. R.; Gowans, G. J.; Hardie, D. G.; Richter, E. A. PT-1 selectively activates AMPK-gamma1 complexes in mouse skeletal muscle, but activates all three gamma subunit complexes in cultured human cells by inhibiting the respiratory chain. Biochem. J. 2015, 467 (3), 461– 472,  DOI: 10.1042/BJ20141142

    Google Scholar

    There is no corresponding record for this reference.
81. 81

    Cool, B.; Zinker, B.; Chiou, W.; Kifle, L.; Cao, N.; Perham, M.; Dickinson, R.; Adler, A.; Gagne, G.; Iyengar, R. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 2006, 3 (6), 403– 416,  DOI: 10.1016/j.cmet.2006.05.005

    Google Scholar

    81

    Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome

    Cool, Barbara; Zinker, Bradley; Chiou, William; Kifle, Lemma; Cao, Ning; Perham, Matthew; Dickinson, Robert; Adler, Andrew; Gagne, Gerard; Iyengar, Rajesh; Zhao, Gang; Marsh, Kennan; Kym, Philip; Jung, Paul; Camp, Heidi S.; Frevert, Ernst

    Cell Metabolism (2006), 3 (6), 403-416CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)

    AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metab. The authors have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 μM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 μM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl Co-A levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidn. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body wt. gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small mol. mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.
82. 82

    Zhao, G.; Iyengar, R. R.; Judd, A. S.; Cool, B.; Chiou, W.; Kifle, L.; Frevert, E.; Sham, H.; Kym, P. R. Discovery and SAR development of thienopyridones: A class of small molecule AMPK activators. Bioorg. Med. Chem. Lett. 2007, 17 (12), 3254– 3257,  DOI: 10.1016/j.bmcl.2007.04.011

    Google Scholar

    There is no corresponding record for this reference.
83. 83

    Sanders, M. J.; Ali, Z. S.; Hegarty, B. D.; Heath, R.; Snowden, M. A.; Carling, D. Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J. Biol. Chem. 2007, 282 (45), 32539– 32548,  DOI: 10.1074/jbc.M706543200

    Google Scholar

    83

    Defining the Mechanism of Activation of AMP-activated Protein Kinase by the Small Molecule A-769662, a Member of the Thienopyridone Family

    Sanders, Matthew J.; Ali, Zahabia S.; Hegarty, Bronwyn D.; Heath, Richard; Snowden, Michael A.; Carling, David

    Journal of Biological Chemistry (2007), 282 (45), 32539-32548CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis. Activation of AMPK in peripheral tissues has been shown to alleviate the symptoms of metabolic diseases, such as type 2 diabetes, and consequently AMPK is a target for treatment of these diseases. Recently, a small mol. activator (A-769662) of AMPK was identified that had beneficial effects on metab. in ob/ob mice. Here we show that A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172, similar to the effects of AMP. A-769662 activates AMPK harboring a mutation in the γ subunit that abolishes activation by AMP. An AMPK complex lacking the glycogen binding domain (GBD) of the β subunit abolishes the allosteric effect of A-769662 but not the allosteric activation by AMP. Moreover, mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the β1 subunit, almost completely abolishes activation of AMPK by A-769662 in cells and in vitro, while only partially reducing activation by AMP. Based on our results we propose a model for activation of AMPK by A-769662. Importantly, this model may provide clues for understanding the mechanism by which AMP leads to activation of AMPK, which in turn may help in the identification of other AMPK activators.
84. 84

    Sujobert, P.; Poulain, L.; Paubelle, E.; Zylbersztejn, F.; Grenier, A.; Lambert, M.; Townsend, E. C.; Brusq, J. M.; Nicodeme, E.; Decrooqc, J. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. Cell Rep 2015, 11 (9), 1446– 1457,  DOI: 10.1016/j.celrep.2015.04.063

    Google Scholar

    There is no corresponding record for this reference.
85. 85

    Jiang, H.; Liu, W.; Zhan, S. K.; Pan, Y. X.; Bian, L. G.; Sun, B.; Sun, Q. F.; Pan, S. J. GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings. PLoS One 2016, 11 (8), e0161017  DOI: 10.1371/journal.pone.0161017

    Google Scholar

    There is no corresponding record for this reference.
86. 86

    Chen, L.; Chen, Q.; Deng, G.; Kuang, S.; Lian, J.; Wang, M.; Zhu, H. AMPK activation by GSK621 inhibits human melanoma cells in vitro and in vivo. Biochem. Biophys. Res. Commun. 2016, 480 (4), 515– 521,  DOI: 10.1016/j.bbrc.2016.10.040

    Google Scholar

    There is no corresponding record for this reference.
87. 87

    Buccinna, B.; Ramondetti, C.; Piccinini, M. AMPK activation attenuates HER3 upregulation and Neuregulin-Mediated rescue of cell proliferation in HER2-Overexpressing breast cancer cell lines exposed to lapatinib. Biochem. Pharmacol. 2022, 204, 115228,  DOI: 10.1016/j.bcp.2022.115228

    Google Scholar

    There is no corresponding record for this reference.
88. 88

    Giordanetto, F.; Karis, D. Direct AMP-activated protein kinase activators: a review of evidence from the patent literature. Expert Opin Ther Pat 2012, 22 (12), 1467– 1477,  DOI: 10.1517/13543776.2012.743994

    Google Scholar

    88

    Direct AMP-activated protein kinase activators: a review of evidence from the patent literature

    Giordanetto, Fabrizio; Karis, David

    Expert Opinion on Therapeutic Patents (2012), 22 (12), 1467-1477CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)

    A review. Introduction: AMP-activated protein kinase (AMPK), a heterotrimeric protein complex with serine/threonine kinase activity has a central role in controlling cellular energy expenditure. Small mol.-based activation of AMPK represents an attractive therapeutic proposition because of AMPK's ability to regulate several anabolic and catabolic pathways that are crit. to the development of metabolic disorders and cancer.Areas covered: A comprehensive review of published patents that disclose direct AMPK activators is provided: 26 patents comprising 10 chem. classes, and supporting in vitro and in vivo data are discussed.Expert opinion: AMPK activation holds promise as a possible pharmacol. intervention in several disease states. The development of direct, highly specific AMPK activators is necessary to fully realize the opportunities linked to AMPK activation and appreciate the risks assocd. with it.
89. 89

    Lai, Y. C.; Kviklyte, S.; Vertommen, D.; Lantier, L.; Foretz, M.; Viollet, B.; Hallen, S.; Rider, M. H. A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators. Biochem. J. 2014, 460 (3), 363– 375,  DOI: 10.1042/BJ20131673

    Google Scholar

    There is no corresponding record for this reference.
90. 90

    Lan, P.; Romero, F. A.; Wodka, D.; Kassick, A. J.; Dang, Q.; Gibson, T.; Cashion, D.; Zhou, G.; Chen, Y.; Zhang, X. Hit-to-Lead Optimization and Discovery of 5-((5-([1,1’-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase. J. Med. Chem. 2017, 60 (21), 9040– 9052,  DOI: 10.1021/acs.jmedchem.7b01344

    Google Scholar

    There is no corresponding record for this reference.
91. 91

    Feng, D.; Biftu, T.; Romero, F. A.; Kekec, A.; Dropinski, J.; Kassick, A.; Xu, S.; Kurtz, M. M.; Gollapudi, A.; Shao, Q. Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase. ACS Med. Chem. Lett. 2018, 9 (1), 39– 44,  DOI: 10.1021/acsmedchemlett.7b00417

    Google Scholar

    91

    Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase

    Feng, Danqing; Biftu, Tesfaye; Romero, F. Anthony; Kekec, Ahmet; Dropinski, James; Kassick, Andrew; Xu, Shiyao; Kurtz, Marc M.; Gollapudi, Anantha; Shao, Qing; Yang, Xiaodong; Lu, Ku; Zhou, Gaochao; Kemp, Daniel; Myers, Robert W.; Guan, Hong-Ping; Trujillo, Maria E.; Li, Cai; Weber, Ann; Sebhat, Iyassu K.

    ACS Medicinal Chemistry Letters (2018), 9 (1), 39-44CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)

    5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and wt. loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. The authors describe the optimization of β1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compds. proved essential in improving β2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration.
92. 92

    Wang, C.; Huang, B.; Sun, L.; Wang, X.; Zhou, B.; Tang, H.; Geng, W. MK8722, an AMPK activator, inhibiting carcinoma proliferation, invasion and migration in human pancreatic cancer cells. Biomed Pharmacother 2021, 144, 112325,  DOI: 10.1016/j.biopha.2021.112325

    Google Scholar

    There is no corresponding record for this reference.
93. 93

    Zadra, G.; Photopoulos, C.; Tyekucheva, S.; Heidari, P.; Weng, Q. P.; Fedele, G.; Liu, H.; Scaglia, N.; Priolo, C.; Sicinska, E. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol. Med. 2014, 6 (4), 519– 538,  DOI: 10.1002/emmm.201302734

    Google Scholar

    There is no corresponding record for this reference.
94. 94

    Cameron, K. O.; Kung, D. W.; Kalgutkar, A. S.; Kurumbail, R. G.; Miller, R.; Salatto, C. T.; Ward, J.; Withka, J. M.; Bhattacharya, S. K.; Boehm, M. Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy. J. Med. Chem. 2016, 59 (17), 8068– 8081,  DOI: 10.1021/acs.jmedchem.6b00866

    Google Scholar

    94

    Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy

    Cameron, Kimberly O.; Kung, Daniel W.; Kalgutkar, Amit S.; Kurumbail, Ravi G.; Miller, Russell; Salatto, Christopher T.; Ward, Jessica; Withka, Jane M.; Bhattacharya, Samit K.; Boehm, Markus; Borzilleri, Kris A.; Brown, Janice A.; Calabrese, Matthew; Caspers, Nicole L.; Cokorinos, Emily; Conn, Edward L.; Dowling, Matthew S.; Edmonds, David J.; Eng, Heather; Fernando, Dilinie P.; Frisbie, Richard; Hepworth, David; Landro, James; Mao, Yuxia; Rajamohan, Francis; Reyes, Allan R.; Rose, Colin R.; Ryder, Tim; Shavnya, Andre; Smith, Aaron C.; Tu, Meihua; Wolford, Angela C.; Xiao, Jun

    Journal of Medicinal Chemistry (2016), 59 (17), 8068-8081CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic assocn. data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compd. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compd. 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.
95. 95

    Edmonds, D. J.; Kung, D. W.; Kalgutkar, A. S.; Filipski, K. J.; Ebner, D. C.; Cabral, S.; Smith, A. C.; Aspnes, G. E.; Bhattacharya, S. K.; Borzilleri, K. A. Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK). J. Med. Chem. 2018, 61 (6), 2372– 2383,  DOI: 10.1021/acs.jmedchem.7b01641

    Google Scholar

    95

    Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5'-Adenosine Monophosphate-Activated Protein Kinase (AMPK)

    Edmonds, David J.; Kung, Daniel W.; Kalgutkar, Amit S.; Filipski, Kevin J.; Ebner, David C.; Cabral, Shawn; Smith, Aaron C.; Aspnes, Gary E.; Bhattacharya, Samit K.; Borzilleri, Kris A.; Brown, Janice A.; Calabrese, Matthew F.; Caspers, Nicole L.; Cokorinos, Emily C.; Conn, Edward L.; Dowling, Matthew S.; Eng, Heather; Feng, Bo; Fernando, Dilinie P.; Genung, Nathan E.; Herr, Michael; Kurumbail, Ravi G.; Lavergne, Sophie Y.; Lee, Esther C.-Y.; Li, Qifang; Mathialagan, Sumathy; Miller, Russell A.; Panteleev, Jane; Polivkova, Jana; Rajamohan, Francis; Reyes, Allan R.; Salatto, Christopher T.; Shavnya, Andre; Thuma, Benjamin A.; Tu, Meihua; Ward, Jessica; Withka, Jane M.; Xiao, Jun; Cameron, Kimberly O.

    Journal of Medicinal Chemistry (2018), 61 (6), 2372-2383CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivs. of the previously described 5-aryl-indole-3-carboxylic acid clin. candidate (1) were examd. with the goal of reducing glucuronidation rate and minimizing renal excretion. Compds. 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclin. species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal org. anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was crit. to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-Ph substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.
96. 96

    Cokorinos, E. C.; Delmore, J.; Reyes, A. R.; Albuquerque, B.; Kjøbsted, R.; Jørgensen, N. O.; Tran, J.-L.; Jatkar, A.; Cialdea, K.; Esquejo, R. M. Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice. Cell Metabolism 2017, 25 (5), 1147– 1159,  DOI: 10.1016/j.cmet.2017.04.010

    Google Scholar

    There is no corresponding record for this reference.
97. 97

    Ngoei, K. R. W.; Langendorf, C. G.; Ling, N. X. Y.; Hoque, A.; Varghese, S.; Camerino, M. A.; Walker, S. R.; Bozikis, Y. E.; Dite, T. A.; Ovens, A. J. Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK alpha2beta2gamma1 by the Glucose Importagog SC4. Cell Chem. Biol. 2018, 25 (6), 728– 737,  DOI: 10.1016/j.chembiol.2018.03.008

    Google Scholar

    There is no corresponding record for this reference.
98. 98

    Grahame Hardie, D. AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J. Intern Med. 2014, 276 (6), 543– 559,  DOI: 10.1111/joim.12268

    Google Scholar

    There is no corresponding record for this reference.
99. 99

    Meley, D.; Bauvy, C.; Houben-Weerts, J. H.; Dubbelhuis, P. F.; Helmond, M. T.; Codogno, P.; Meijer, A. J. AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem. 2006, 281 (46), 34870– 34879,  DOI: 10.1074/jbc.M605488200

    Google Scholar

    There is no corresponding record for this reference.
100. 100

     Bain, J.; Plater, L.; Elliott, M.; Shpiro, N.; Hastie, C. J.; McLauchlan, H.; Klevernic, I.; Arthur, J. S.; Alessi, D. R.; Cohen, P. The selectivity of protein kinase inhibitors: a further update. Biochem. J. 2007, 408 (3), 297– 315,  DOI: 10.1042/BJ20070797

     Google Scholar

     100

     The selectivity of protein kinase inhibitors: a further update

     Bain, Jenny; Plater, Lorna; Elliott, Matt; Shpiro, Natalia; Hastie, C. James; McLauchlan, Hilary; Klevernic, Iva; Arthur, J. Simon C.; Alessi, Dario R.; Cohen, Philip

     Biochemical Journal (2007), 408 (3), 297-315CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)

     The specificities of 65 compds. reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70-80 protein kinases. On the basis of this information, the effects of compds. that we have studied in cells and other data in the literature, we recommend the use of the following small-mol. inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiol. roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)-raptor (regulatory assocd. protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-mol. inhibitors of protein kinases to assess the physiol. roles of these enzymes. Despite being used widely, many of the compds. that we analyzed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.
101. 101

     Liu, X.; Chhipa, R. R.; Nakano, I.; Dasgupta, B. The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent. Molecular cancer therapeutics 2014, 13 (3), 596– 605,  DOI: 10.1158/1535-7163.MCT-13-0579

     Google Scholar

     There is no corresponding record for this reference.
102. 102

     Emerling, B. M.; Viollet, B.; Tormos, K. V.; Chandel, N. S. Compound C inhibits hypoxic activation of HIF-1 independent of AMPK. FEBS Lett. 2007, 581 (29), 5727– 5731,  DOI: 10.1016/j.febslet.2007.11.038

     Google Scholar

     There is no corresponding record for this reference.
103. 103

     Egan, D. F.; Chun, M. G.; Vamos, M.; Zou, H.; Rong, J.; Miller, C. J.; Lou, H. J.; Raveendra-Panickar, D.; Yang, C. C.; Sheffler, D. J. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Mol. Cell 2015, 59 (2), 285– 297,  DOI: 10.1016/j.molcel.2015.05.031

     Google Scholar

     103

     Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates

     Egan, Daniel F.; Chun, Matthew G. H.; Vamos, Mitchell; Zou, Haixia; Rong, Juan; Miller, Chad J.; Lou, Hua Jane; Raveendra-Panickar, Dhanya; Yang, Chih-Cheng; Sheffler, Douglas J.; Teriete, Peter; Asara, John M.; Turk, Benjamin E.; Cosford, Nicholas D. P.; Shaw, Reuben J.

     Molecular Cell (2015), 59 (2), 285-297CODEN: MOCEFL; ISSN:1097-2765. (Elsevier Inc.)

     Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small mol. inhibitor. The compd. SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.
104. 104

     Ahwazi, D.; Neopane, K.; Markby, G. R.; Kopietz, F.; Ovens, A. J.; Dall, M.; Hassing, A. S.; Grasle, P.; Alshuweishi, Y.; Treebak, J. T. Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965. Biochem. J. 2021, 478 (15), 2977– 2997,  DOI: 10.1042/BCJ20210284

     Google Scholar

     There is no corresponding record for this reference.
105. 105

     Tang, F.; Hu, P.; Yang, Z.; Xue, C.; Gong, J.; Sun, S.; Shi, L.; Zhang, S.; Li, Z.; Yang, C. SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways. Oncol. Rep. 2017, 37 (6), 3449– 3458,  DOI: 10.3892/or.2017.5635

     Google Scholar

     105

     SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways

     Tang, Fang; Hu, Pengchao; Yang, Zetian; Xue, Chao; Gong, Jun; Sun, Shaoxing; Shi, Liu; Zhang, Shimin; Li, Zhenzhen; Yang, Chunxu; Zhang, Junhong; Xie, Conghua

     Oncology Reports (2017), 37 (6), 3449-3458CODEN: OCRPEW; ISSN:1791-2431. (Spandidos Publications Ltd.)

     Lung cancer is a major public health problem worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. Autophagy has recently sparked great interest, and it is thought to participate in a variety of diseases, including lung cancer. Uncoordinated (Unc) 51-like kinase 1 (Ulk1), a serine/threonine kinase, plays a central role in the autophagy pathway. However, the role of Ulk1 in NSCLC remains unclear. We report that NSCLC cell lines exhibited high expression of Ulk1 and that Ulk1 was neg. correlated with prognosis in lung cancer patients. Knockdown of Ulk1 or the inhibition of Ulk1 by the selective inhibitor SBI0206965, inhibited cell proliferation, induced cell apoptosis and enhanced the sensitivity of cisplatin against NSCLC cells. Moreover, we demonstrated that Ulk1 exerted oncogenic activity in NSCLC by modulating both autophagy and apoptosis pathways. Inhibition of autophagy by SBI0206965 sensitized NSCLC cells to cisplatin by inhibiting cisplatin induced cell-protective autophagy to promote apoptosis. Furthermore, SBI0206965 promoted apoptosis in NSCLC cells independent of autophagy, which was partly mediated by destabilization of Bcl2/Bclxl. In summary, our results show that inhibition of Ulk1 suppresses NSCLC cell growth and sensitizes NSCLC cells to cisplatin by modulating both autophagy and apoptosis pathways, and that Ulk1 might be a promising target for NSCLC treatment.
106. 106

     Lin, C.; Blessing, A. M.; Pulliam, T. L.; Shi, Y.; Wilkenfeld, S. R.; Han, J. J.; Murray, M. M.; Pham, A. H.; Duong, K.; Brun, S. N. Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling. Oncogene 2021, 40 (9), 1690– 1705,  DOI: 10.1038/s41388-021-01658-z

     Google Scholar

     There is no corresponding record for this reference.
107. 107

     Desai, J. M.; Karve, A. S.; Gudelsky, G. A.; Gawali, M. V.; Seibel, W.; Sallans, L.; DasGupta, B.; Desai, P. B. Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma. Invest New Drugs 2022, 40 (5), 944– 952,  DOI: 10.1007/s10637-022-01278-8

     Google Scholar

     There is no corresponding record for this reference.
108. 108

     Motzer, R. J.; Escudier, B.; Gannon, A.; Figlin, R. A. Sunitinib: Ten Years of Successful Clinical Use and Study in Advanced Renal Cell Carcinoma. Oncologist 2017, 22 (1), 41– 52,  DOI: 10.1634/theoncologist.2016-0197

     Google Scholar

     There is no corresponding record for this reference.
109. 109

     Gridelli, C.; Maione, P.; Del Gaizo, F.; Colantuoni, G.; Guerriero, C.; Ferrara, C.; Nicolella, D.; Comunale, D.; De Vita, A.; Rossi, A. Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. oncologist 2007, 12 (2), 191– 200,  DOI: 10.1634/theoncologist.12-2-191

     Google Scholar

     There is no corresponding record for this reference.
110. 110

     Polyzos, A. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma and various other solid tumors. Journal of steroid biochemistry and molecular biology 2008, 108 (3–5), 261– 266,  DOI: 10.1016/j.jsbmb.2007.09.004

     Google Scholar

     There is no corresponding record for this reference.
111. 111

     Laderoute, K. R.; Calaoagan, J. M.; Madrid, P. B.; Klon, A. E.; Ehrlich, P. J. SU11248 (sunitinib) directly inhibits the activity of mammalian 5′-AMP-activated protein kinase (AMPK). Cancer Biol. Ther 2010, 10 (1), 68– 76,  DOI: 10.4161/cbt.10.1.12162

     Google Scholar

     There is no corresponding record for this reference.
112. 112

     Davis, M. I.; Hunt, J. P.; Herrgard, S.; Ciceri, P.; Wodicka, L. M.; Pallares, G.; Hocker, M.; Treiber, D. K.; Zarrinkar, P. P. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 2011, 29 (11), 1046– 1051,  DOI: 10.1038/nbt.1990

     Google Scholar

     112

     Comprehensive analysis of kinase inhibitor selectivity

     Davis, Mindy I.; Hunt, Jeremy P.; Herrgard, Sanna; Ciceri, Pietro; Wodicka, Lisa M.; Pallares, Gabriel; Hocker, Michael; Treiber, Daniel K.; Zarrinkar, Patrick P.

     Nature Biotechnology (2011), 29 (11), 1046-1051CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)

     We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compds. tested. Anal. of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compds. to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biol. and toxicity, as well as for studying the structural basis of the obsd. interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
113. 113

     Kerkela, R.; Woulfe, K. C.; Durand, J. B.; Vagnozzi, R.; Kramer, D.; Chu, T. F.; Beahm, C.; Chen, M. H.; Force, T. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clinical and translational science 2009, 2 (1), 15– 25,  DOI: 10.1111/j.1752-8062.2008.00090.x

     Google Scholar

     There is no corresponding record for this reference.
114. 114

     Force, T.; Krause, D. S.; Van Etten, R. A. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat. Rev. Cancer 2007, 7 (5), 332– 344,  DOI: 10.1038/nrc2106

     Google Scholar

     114

     Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

     Force, Thomas; Krause, Daniela S.; Van Etten, Richard A.

     Nature Reviews Cancer (2007), 7 (5), 332-344CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)

     A review. Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of 'targeted therapies', particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been assocd. with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.
115. 115

     Georgievska, B.; Sandin, J.; Doherty, J.; Mortberg, A.; Neelissen, J.; Andersson, A.; Gruber, S.; Nilsson, Y.; Schott, P.; Arvidsson, P. I. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J. Neurochem 2013, 125 (3), 446– 456,  DOI: 10.1111/jnc.12203

     Google Scholar

     There is no corresponding record for this reference.
116. 116

     Ross, F. A.; Hawley, S. A.; Auciello, F. R.; Gowans, G. J.; Atrih, A.; Lamont, D. J.; Hardie, D. G. Mechanisms of Paradoxical Activation of AMPK by the Kinase Inhibitors SU6656 and Sorafenib. Cell Chem. Biol. 2017, 24 (7), 813– 824,  DOI: 10.1016/j.chembiol.2017.05.021

     Google Scholar

     There is no corresponding record for this reference.
117. 117

     Li, X.; Wang, L.; Zhou, X. E.; Ke, J.; de Waal, P. W.; Gu, X.; Tan, M. H.; Wang, D.; Wu, D.; Xu, H. E. Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res. 2015, 25 (1), 50– 66,  DOI: 10.1038/cr.2014.150

     Google Scholar

     117

     Structural basis of AMPK regulation by adenine nucleotides and glycogen

     Li, Xiaodan; Wang, Lili; Zhou, X. Edward; Ke, Jiyuan; de Waal, Parker W.; Gu, Xin; Tan, M. H. Eileen; Wang, Dongye; Wu, Donghai; Xu, H. Eric; Melcher, Karsten

     Cell Research (2015), 25 (1), 50-66CODEN: CREEB6; ISSN:1001-0602. (NPG Nature Asia-Pacific)

     AMP-activated protein kinase (AMPK) is a central cellular energy sensor and regulator of energy homeostasis, and a promising drug target for the treatment of diabetes, obesity, and cancer. Here we present low-resoln. crystal structures of the human α1β2γ1 holo-AMPK complex bound to its allosteric modulators AMP and the glycogen-mimic cyclodextrin, both in the phosphorylated (4.05 Å) and non-phosphorylated (4.60 Å) state. In addn., we have solved a 2.95 Å structure of the human kinase domain (KD) bound to the adjacent autoinhibitory domain (AID) and have performed extensive biochem. and mutational studies. Together, these studies illustrate an underlying mechanism of allosteric AMPK modulation by AMP and glycogen, whose binding changes the equil. between alternate AID (AMP) and carbohydrate-binding module (glycogen) interactions.
118. 118

     Hawley, S. A.; Russell, F. M.; Ross, F. A.; Hardie, D. G. BAY-3827 and SBI-0206965: Potent AMPK Inhibitors That Paradoxically Increase Thr172 Phosphorylation. Int. J. Mol. Sci. 2024, 25 (1), 453,  DOI: 10.3390/ijms25010453

     Google Scholar

     There is no corresponding record for this reference.
119. 119

     Laderoute, K. R.; Amin, K.; Calaoagan, J. M.; Knapp, M.; Le, T.; Orduna, J.; Foretz, M.; Viollet, B. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol. Cell. Biol. 2006, 26 (14), 5336– 5347,  DOI: 10.1128/MCB.00166-06

     Google Scholar

     There is no corresponding record for this reference.
120. 120

     Sharma, A.; Arambula, J. F.; Koo, S.; Kumar, R.; Singh, H.; Sessler, J. L.; Kim, J. S. Hypoxia-targeted drug delivery. Chem. Soc. Rev. 2019, 48 (3), 771– 813,  DOI: 10.1039/C8CS00304A

     Google Scholar

     120

     Hypoxia-targeted drug delivery

     Sharma, Amit; Arambula, Jonathan F.; Koo, Seyoung; Kumar, Rajesh; Singh, Hardev; Sessler, Jonathan L.; Kim, Jong Seung

     Chemical Society Reviews (2019), 48 (3), 771-813CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

     A review. Hypoxia is a state of low oxygen tension found in numerous solid tumors. It is typically assocd. with abnormal vasculature, which results in a reduced supply of oxygen and nutrients, as well as impaired delivery of drugs. The hypoxic nature of tumors often leads to the development of localized heterogeneous environments characterized by variable oxygen concns., relatively low pH, and increased levels of reactive oxygen species (ROS). The hypoxic heterogeneity promotes tumor invasiveness, metastasis, angiogenesis, and an increase in multidrug-resistant proteins. These factors decrease the therapeutic efficacy of anticancer drugs and can provide a barrier to advancing drug leads beyond the early stages of preclin. development. This review highlights various hypoxia-targeted and activated design strategies for the formulation of drugs or prodrugs and their mechanism of action for tumor diagnosis and treatment.
121. 121

     Zheng, Y.; Liu, L.; Wang, Y.; Xiao, S.; Mai, R.; Zhu, Z.; Cao, Y. Glioblastoma stem cell (GSC)-derived PD-L1-containing exosomes activates AMPK/ULK1 pathway mediated autophagy to increase Temozolomide-resistance in glioblastoma. Cell Biosci 2021, 11 (1), 63,  DOI: 10.1186/s13578-021-00575-8

     Google Scholar

     There is no corresponding record for this reference.
122. 122

     Andugulapati, S. B.; Sundararaman, A.; Lahiry, M.; Rangarajan, A. AMP-activated protein kinase promotes breast cancer stemness and drug resistance. Dis Model Mech 2022, 15 (6), dmm049203,  DOI: 10.1242/dmm.049203

     Google Scholar

     There is no corresponding record for this reference.