ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer

View Author Information
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
Piramed Pharma, 957 Buckingham Avenue, Slough, Berks SL1 4NL, United Kingdom
Phone: 650-225-3171. Fax: 650-225-2061. E-mail: [email protected]
Cite this: J. Med. Chem. 2011, 54, 21, 7579–7587
Publication Date (Web):October 7, 2011
Copyright © 2011 American Chemical Society

    Article Views





    Other access options


    Abstract Image

    The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC50s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a Ki of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Cited By

    This article is cited by 169 publications.

    1. Kewalin Posansee, Monrudee Liangruksa, Teerasit Termsaithong, Patchreenart Saparpakorn, Supa Hannongbua, Teeraphan Laomettachit, Thana Sutthibutpong. Combined Deep Learning and Molecular Modeling Techniques on the Virtual Screening of New mTOR Inhibitors from the Thai Mushroom Database. ACS Omega 2023, 8 (41) , 38373-38385.
    2. Jindi Huang, Liye Chen, Jiangxia Wu, Daiqiao Ai, Ji-Quan Zhang, Tie-Gen Chen, Ling Wang. Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions. Journal of Medicinal Chemistry 2022, 65 (24) , 16033-16061.
    3. Xiangqian Li, Xiaowei Li, Fang Liu, Shuo Li, Dayong Shi. Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist. Journal of Medicinal Chemistry 2021, 64 (15) , 10581-10605.
    4. Junwei Wang, Hui Li, Guangchao He, Zhaoxing Chu, Kewen Peng, Yiran Ge, Qihua Zhu, Yungen Xu. Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy. Journal of Medicinal Chemistry 2020, 63 (1) , 122-139.
    5. Denise Rageot, Thomas Bohnacker, Erhan Keles, Jacob A. McPhail, Reece M. Hoffmann, Anna Melone, Chiara Borsari, Rohitha Sriramaratnam, Alexander M. Sele, Florent Beaufils, Paul Hebeisen, Doriano Fabbro, Petra Hillmann, John E. Burke, Matthias P. Wymann. (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase. Journal of Medicinal Chemistry 2019, 62 (13) , 6241-6261.
    6. Aimie E. Garces, Michael J. Stocks. Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective. Journal of Medicinal Chemistry 2019, 62 (10) , 4815-4850.
    7. Rémy Angelaud Steve Staben Timothy Heffron Andreas Schuster Frédéric St-Jean . From Discovery to Market Readiness: The Research and Development of the β-Sparing Phosphatidylinositol 3-Kinase Inhibitor Taselisib. 2019, 61-83.
    8. Tao Yu, Ning Li, Chengde Wu, Amy Guan, Yi Li, Zhengang Peng, Miao He, Jie Li, Zhen Gong, Lei Huang, Bo Gao, Dongling Hao, Jikui Sun, Yan Pan, Liang Shen, Chichung Chan, Xiulian Lu, Hongyu Yuan, Yongguo Li, Jian Li, Shuhui Chen. Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR. ACS Medicinal Chemistry Letters 2018, 9 (3) , 256-261.
    9. Qingxiang Guo, Chenhua Yu, Chao Zhang, Yongtao Li, Tianqi Wang, Zhi Huang, Xin Wang, Wei Zhou, Yao Li, Zhongxiang Qin, Cheng Wang, Ruifang Gao, Yongwei Nie, Yakun Ma, Yi Shi, Jianyu Zheng, Shengyong Yang, Yan Fan, and Rong Xiang . Highly Selective, Potent, and Oral mTOR Inhibitor for Treatment of Cancer as Autophagy Inducer. Journal of Medicinal Chemistry 2018, 61 (3) , 881-904.
    10. Florent Beaufils, Natasa Cmiljanovic, Vladimir Cmiljanovic, Thomas Bohnacker, Anna Melone, Romina Marone, Eileen Jackson, Xuxiao Zhang, Alexander Sele, Chiara Borsari, Jürgen Mestan, Paul Hebeisen, Petra Hillmann, Bernd Giese, Marketa Zvelebil, Doriano Fabbro, Roger L. Williams, Denise Rageot, and Matthias P. Wymann . 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology. Journal of Medicinal Chemistry 2017, 60 (17) , 7524-7538.
    11. Chengbin Yang, Xi Zhang, Yi Wang, Yongtai Yang, Xiaofeng Liu, Mingli Deng, Yu Jia, Yun Ling, Ling-hua Meng, and Yaming Zhou . Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity. ACS Medicinal Chemistry Letters 2017, 8 (8) , 875-880.
    12. Miao Zhan, Yufang Deng, Lifeng Zhao, Guoyi Yan, Fangying Wang, Ye Tian, Lanxi Zhang, Hongxia Jiang, and Yuanwei Chen . Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors. Journal of Medicinal Chemistry 2017, 60 (9) , 4023-4035.
    13. Yong Chen, Xiaoyan Wang, Wei Xiang, Lin He, Minghai Tang, Fang Wang, Taijin Wang, Zhuang Yang, Yuyao Yi, Hairong Wang, Ting Niu, Li Zheng, Lei Lei, Xiaobin Li, Hang Song, and Lijuan Chen . Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities. Journal of Medicinal Chemistry 2016, 59 (11) , 5488-5504.
    14. Timothy P. Heffron, Chudi O. Ndubaku, Laurent Salphati, Bruno Alicke, Jonathan Cheong, Joy Drobnick, Kyle Edgar, Stephen E. Gould, Leslie B. Lee, John D. Lesnick, Cristina Lewis, Jim Nonomiya, Jodie Pang, Emile G. Plise, Steve Sideris, Jeffrey Wallin, Lan Wang, Xiaolin Zhang, and Alan G. Olivero . Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Medicinal Chemistry Letters 2016, 7 (4) , 351-356.
    15. Timothy P. Heffron, Robert A. Heald, Chudi Ndubaku, BinQing Wei, Martin Augistin, Steven Do, Kyle Edgar, Charles Eigenbrot, Lori Friedman, Emanuela Gancia, Philip S. Jackson, Graham Jones, Aleksander Kolesnikov, Leslie B. Lee, John D. Lesnick, Cristina Lewis, Neville McLean, Mario Mörtl, Jim Nonomiya, Jodie Pang, Steve Price, Wei Wei Prior, Laurent Salphati, Steve Sideris, Steven T. Staben, Stefan Steinbacher, Vickie Tsui, Jeffrey Wallin, Deepak Sampath, and Alan G. Olivero . The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326). Journal of Medicinal Chemistry 2016, 59 (3) , 985-1002.
    16. Timothy P. Heffron Andrew McClory Andreas Stumpf . The Discovery and Process Chemistry Development of GDC-0084, a Brain Penetrating Inhibitor of PI3K and mTOR. 2016, 147-173.
    17. Srinivasan Babu Francis Gosselin Theresa Humphries Alan Olivero Daniel Sutherlin Qingping Tian . Discovery and Process Development of Class I PI3K and Class I PI3K/mTOR Inhibitors GDC-0941 and GDC-0980. 2016, 237-270.
    18. Qingping Tian, Ursula Hoffmann, Theresa Humphries, Zhigang Cheng, Pirmin Hidber, Herbert Yajima, Maud Guillemot-Plass, Jane Li, Ulrike Bromberger, Srinivasan Babu, David Askin, and Francis Gosselin . A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor. Organic Process Research & Development 2015, 19 (3) , 416-426.
    19. Martin Andrs, Jan Korabecny, Daniel Jun, Zdenek Hodny, Jiri Bartek, and Kamil Kuca . Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring. Journal of Medicinal Chemistry 2015, 58 (1) , 41-71.
    20. Chudi O. Ndubaku, Timothy P. Heffron, Steven T. Staben, Matthew Baumgardner, Nicole Blaquiere, Erin Bradley, Richard Bull, Steven Do, Jennafer Dotson, Danette Dudley, Kyle A. Edgar, Lori S. Friedman, Richard Goldsmith, Robert A. Heald, Aleksandr Kolesnikov, Leslie Lee, Cristina Lewis, Michelle Nannini, Jim Nonomiya, Jodie Pang, Steve Price, Wei Wei Prior, Laurent Salphati, Steve Sideris, Jeffery J. Wallin, Lan Wang, BinQing Wei, Deepak Sampath, and Alan G. Olivero . Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity. Journal of Medicinal Chemistry 2013, 56 (11) , 4597-4610.
    21. Craig S. Takeuchi, Byung Gyu Kim, Charles M. Blazey, Sunghoon Ma, Henry W. B. Johnson, Neel K. Anand, Arlyn Arcalas, Tae Gon Baik, Chris A. Buhr, Jonah Cannoy, Sergey Epshteyn, Anagha Joshi, Katherine Lara, Matthew S. Lee, Longcheng Wang, James W. Leahy, John M. Nuss, Naing Aay, Ron Aoyama, Paul Foster, Jae Lee, Isabelle Lehoux, Narsimha Munagala, Arthur Plonowski, Sharmila Rajan, John Woolfrey, Kyoko Yamaguchi, Peter Lamb, and Nicole Miller . Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR). Journal of Medicinal Chemistry 2013, 56 (6) , 2218-2234.
    22. Michael F. T. Koehler, Philippe Bergeron, Elizabeth Blackwood, Krista K. Bowman, Yung-Hsiang Chen, Gauri Deshmukh, Xiao Ding, Jennifer Epler, Kevin Lau, Leslie Lee, Lichuan Liu, Cuong Ly, Shiva Malek, Jim Nonomiya, Jason Oeh, Daniel F. Ortwine, Deepak Sampath, Steve Sideris, Lan Trinh, Tom Truong, Jiansheng Wu, Zhonghua Pei, and Joseph P. Lyssikatos . Potent, Selective, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin Kinase Domain Exhibiting Single Agent Antiproliferative Activity. Journal of Medicinal Chemistry 2012, 55 (24) , 10958-10971.
    23. Timothy P. Heffron, Laurent Salphati, Bruno Alicke, Jonathan Cheong, Jennafer Dotson, Kyle Edgar, Richard Goldsmith, Stephen E. Gould, Leslie B. Lee, John D. Lesnick, Cristina Lewis, Chudi Ndubaku, Jim Nonomiya, Alan G. Olivero, Jodie Pang, Emile G. Plise, Steve Sideris, Sean Trapp, Jeffrey Wallin, Lan Wang, and Xiaolin Zhang . The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α. Journal of Medicinal Chemistry 2012, 55 (18) , 8007-8020.
    24. Irina A. Gorbunova, Anna Rogova, Darya R. Akhmetova, Roman Yu. Sidorov, Eugene E. Priakhin, Ramiz R. Makhmudov, Daria A. Shipilovskikh, Olga S. Epifanovskaya, Alexander S. Timin, Sergei A. Shipilovskikh. Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies. Bioorganic Chemistry 2024, 148 , 107468.
    25. Yiren Yang, Yi Mou, Lin‐Xi Wan, Shiou Zhu, Guan Wang, Huiyuan Gao, Bo Liu. Rethinking therapeutic strategies of dual‐target drugs: An update on pharmacological small‐molecule compounds in cancer. Medicinal Research Reviews 2024, 20
    26. Vankayala Ramesh Babu, Singamsetty Rangaswamy, SVVNSM Lakshmi, Murali Musuluri, Kit-Kay Mak, Tasqeeruddin Syed, Bavisetti Lakshmi, V.D.N. Kumar Abbaraju. Design, Synthesis, Anticancer Evaluation and Molecular Docking Studies of Amide Derivatives of Thienopyrimidine Isoxazoles. Organic Preparations and Procedures International 2024, , 1-12.
    27. Dima A. Sabbah, Rima Hajjo, Sanaa K. Bardaweel, Haizhen A. Zhong. Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023). Expert Opinion on Therapeutic Patents 2024, 34 (3) , 141-158.
    28. Mengjia Jiang, Wayne Wu, Zijie Xiong, Xiaoping Yu, Zihong Ye, Zhiping Wu. Targeting autophagy drug discovery: Targets, indications and development trends. European Journal of Medicinal Chemistry 2024, 267 , 116117.
    29. Jiarui Hu, Siyu Fu, Zixuan Zhan, Jifa Zhang. Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects. European Journal of Medicinal Chemistry 2024, 265 , 116109.
    30. Yang Yang, Xin Sun, Leixuan Luo, Rujue Peng, Ruiqing Yang, Zhenjie Cheng, Yao Lv, Hongfeng Li, Qidong Tang, Wufu Zhu, Dan Qiao, Shan Xu. Discovery of novel potent PI3K/mTOR dual‐target inhibitors based on scaffold hopping: Design, synthesis, and antiproliferative activity. Archiv der Pharmazie 2023, 356 (12)
    31. Leixuan Luo, Xin Sun, Yang Yang, Lulu Xia, Shiyu Wang, Yuxing Fu, Yuxuan Zhu, Shan Xu, Wufu Zhu. A Novel Dual PI3K/mTOR Inhibitor, XIN-10, for the Treatment of Cancer. International Journal of Molecular Sciences 2023, 24 (19) , 14821.
    32. Shuai Wang, Jian-Tao Shi, Xing-Rong Wang, Hong-Xia Mu, Xue-Ting Wang, Kai-Yan Xu, Qing-Shan Wang, Shi-Wu Chen. 1H-Indazoles derivatives targeting PI3K/AKT/mTOR pathway: Synthesis, anti-tumor effect and molecular mechanism. Bioorganic Chemistry 2023, 133 , 106412.
    33. Yu Wang, Yajing Liu, Tingjie Ge, Jiechun Tang, Shihui Wang, Zhanfeng Gao, Jiaxu Chen, Jundong Xu, Ping Gong, Yanfang Zhao, Jiuyu Liu, Yunlei Hou. Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors. Bioorganic Chemistry 2023, 130 , 106211.
    34. Dorota Stary, Eugenie Nepovimova, Kamil Kuca, Marek Bajda. Searching for new mTOR kinase inhibitors: Analysis of binding sites and validation of docking protocols. Chemical Biology & Drug Design 2023, 101 (1) , 103-119.
    35. Shan Xu, Leixuan Luo, Xin Sun, Yang Yang, Qiuyan Guo, Zhiyan Jiang, Yingliang Wu. Design, synthesis and antitumor activity of novel thiophene- triazine derivatives bearing arylurea unit as potent PI3K/mTOR inhibitorss. Bioorganic & Medicinal Chemistry 2023, 78 , 117133.
    36. Yingmin Jiang, Wendian Xiong, Lei Jia, Lei Xu, Yanfei Cai, Yun Chen, Jian Jin, Mingzhu Gao, Jingyu Zhu. Developing a Naïve Bayesian Classification Model with PI3Kγ structural features for virtual screening against PI3Kγ: Combining molecular docking and pharmacophore based on multiple PI3Kγ conformations. European Journal of Medicinal Chemistry 2022, 244 , 114824.
    37. Xin Sun, Binliang Zhang, Leixuan Luo, Yang Yang, Bin He, Qian Zhang, Linxiao Wang, Shan Xu, Pengwu Zheng, Wufu Zhu. Design, synthesis and pharmacological evaluation of 2-arylurea-1,3,5-triazine derivative (XIN-9): A novel potent dual PI3K/mTOR inhibitor for cancer therapy. Bioorganic Chemistry 2022, 129 , 106157.
    38. Abdalla R. Mohamed, Ahmed M. El Kerdawy. A Perspective Study on the RTK, PI3K, B‐Raf, CDK and the Multi‐Protein Targeting in Medicinal Chemistry. Chemistry & Biodiversity 2022, 19 (10)
    39. Mariola Stypik, Marcin Zagozda, Stanisław Michałek, Barbara Dymek, Daria Zdżalik-Bielecka, Maciej Dziachan, Nina Orłowska, Paweł Gunerka, Paweł Turowski, Joanna Hucz-Kalitowska, Aleksandra Stańczak, Paulina Stańczak, Krzysztof Mulewski, Damian Smuga, Filip Stefaniak, Lidia Gurba-Bryśkiewicz, Arkadiusz Leniak, Zbigniew Ochal, Mateusz Mach, Karolina Dzwonek, Monika Lamparska-Przybysz, Krzysztof Dubiel, Maciej Wieczorek. Design, Synthesis, and Development of pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part I—Indole Derivatives. Pharmaceuticals 2022, 15 (8) , 949.
    40. Beibei Mao, Qi Zhang, Li Ma, Dong-Sheng Zhao, Pan Zhao, Peizheng Yan. Overview of Research into mTOR Inhibitors. Molecules 2022, 27 (16) , 5295.
    41. M Koteswaraiah, Ch Praveen, Thummaluru Veera reddy, Gopireddy Raveendrareddy, Uppalanchi Srinivas. Design, synthesis and biological evaluation of aryl and hetero-aryl linked thieno[3,2-d]pyrimidine derivatives as anticancer agents. Chemical Data Collections 2022, 39 , 100863.
    42. Monica M. Kangussu-Marcolino, Upinder Singh. Ponatinib, Lestaurtinib, and mTOR/PI3K Inhibitors Are Promising Repurposing Candidates against Entamoeba histolytica. Antimicrobial Agents and Chemotherapy 2022, 66 (2)
    43. Amir Barzegar Behrooz, Zahra Talaie, Fatemeh Jusheghani, Marek J. Łos, Thomas Klonisch, Saeid Ghavami. Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma. International Journal of Molecular Sciences 2022, 23 (3) , 1353.
    44. Yuanze Wang, Micky Tortorella. Molecular design of dual inhibitors of PI3K and potential molecular target of cancer for its treatment: A review. European Journal of Medicinal Chemistry 2022, 228 , 114039.
    45. Wioleta Justyna Omeljaniuk, Rafał Krętowski, Wioletta Ratajczak-Wrona, Ewa Jabłońska, Marzanna Cechowska-Pasko. Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells. International Journal of Molecular Sciences 2021, 22 (21) , 11511.
    46. Ahmed M. Farghaly, Omaima M. AboulWafa, Hoda H. Baghdadi, Heba A. Abd El Razik, Samir M.Y. Sedra, Marium M. Shamaa. New thieno[3,2-d]pyrimidine-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents, EGFR and ARO inhibitors inducing apoptosis in breast cancer cells. Bioorganic Chemistry 2021, 115 , 105208.
    47. Chiara Borsari, Martina De Pascale, Matthias P. Wymann. Chemical and Structural Strategies to Selectively Target mTOR Kinase. ChemMedChem 2021, 16 (18) , 2744-2759.
    48. Eclair Venturini Filho, Jorge W.S. Pina, Mariana K. Antoniazi, Laiza B. Loureiro, Marcos A. Ribeiro, Carlos B. Pinheiro, Celina J. Guimarães, Fátima C.E. de Oliveira, Claudia Pessoa, Alex G. Taranto, Sandro J. Greco. Synthesis, docking, machine learning and antiproliferative activity of the 6-ferrocene/heterocycle-2-aminopyrimidine and 5-ferrocene-1H-Pyrazole derivatives obtained by microwave-assisted Atwal reaction as potential anticancer agents. Bioorganic & Medicinal Chemistry Letters 2021, 48 , 128240.
    49. Pankaj Sharma, Chris LaRosa, Janet Antwi, Rajgopal Govindarajan, Karl A. Werbovetz. Imidazoles as Potential Anticancer Agents: An Update on Recent Studies. Molecules 2021, 26 (14) , 4213.
    50. Ruoyu He, Bingyong Xu, Li Ping, Xiaoqing Lv. Structural optimization towards promising β-methyl-4-acrylamido quinoline derivatives as PI3K/mTOR dual inhibitors for anti-cancer therapy: The in vitro and in vivo biological evaluation. European Journal of Medicinal Chemistry 2021, 214 , 113249.
    51. Abdalla R. Mohamed, Ahmed M. El Kerdawy, Riham F. George, Hanan H. Georgey, Nagwa M. Abdel Gawad. Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities. Bioorganic Chemistry 2021, 107 , 104569.
    52. Yifan Chen, Xiaoping Zhou. Research progress of mTOR inhibitors. European Journal of Medicinal Chemistry 2020, 208 , 112820.
    53. Lingzhi Zhang, Qiurong Ju, Jinjin Sun, Lei Huang, Shiqi Wu, Shuping Wang, Yin Li, Zhe Guan, Qihua Zhu, Yungen Xu. Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy. Molecules 2020, 25 (23) , 5693.
    54. Liang Xia, Yan Zhang, Jingbo Zhang, Songwen Lin, Kehui Zhang, Hua Tian, Yi Dong, Heng Xu. Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors. Molecules 2020, 25 (20) , 4630.
    55. Dong Kee Jang, Yu Geon Lee, Young Chan Chae, Jun Kyu Lee, Woo Hyun Paik, Sang Hyub Lee, Yong-Tae Kim, Ji Kon Ryu. GDC-0980 (apitolisib) treatment with gemcitabine and/or cisplatin synergistically reduces cholangiocarcinoma cell growth by suppressing the PI3K/Akt/mTOR pathway. Biochemical and Biophysical Research Communications 2020, 529 (4) , 1242-1248.
    56. Narittira Ornnork, Duangnapa Kiriwan, Kriengsak Lirdprapamongkol, Kiattawee Choowongkomon, Jisnuson Svasti, Chatchakorn Eurtivong. Molecular dynamics, MM/PBSA and in vitro validation of a novel quinazoline-based EGFR tyrosine kinase inhibitor identified using structure-based in silico screening. Journal of Molecular Graphics and Modelling 2020, 99 , 107639.
    57. Minhang Xin, Hui-Yan Wang, Hao Zhang, Ying Shen, San-Qi Zhang. Synthesis and biological activity of new 2,4,6-trisubstituted triazines as potential phosphoinositide 3-kinase inhibitors. Journal of Chemical Research 2020, 44 (7-8) , 393-402.
    58. Ru-Yi Jin, Tian Tang, Sha Zhou, Xu Long, Hui Guo, Jing Zhou, Hao Yan, Zhi Li, Zheng-Yu Zuo, Hong-Lei Xie, Yu-Ping Tang. Design, synthesis, antitumor activity and theoretical calculation of novel PI3Ka inhibitors. Bioorganic Chemistry 2020, 98 , 103737.
    59. Xingrong Liu, Xiaorong Liang, Jenninfer LeCouter, Savita Ubhayakar, Jacob Chen, Jay Cheng, Tom Lee, Joe Lubach, Jim Nonomiya, Sheerin Shahidi-Latham, Cristine Quiason, Eric Solon, Matthew Wright, Cornelis E.C.A. Hop, Timothy P. Heffron. Characterization of Antineovascularization Activity and Ocular Pharmacokinetics of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GNE-947. Drug Metabolism and Disposition 2020, 48 (5) , 408-419.
    60. Archana Kumari, Rajesh K. Singh. Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the structure-activity relationship (SAR). Bioorganic Chemistry 2020, 96 , 103578.
    61. Ying-Qi Feng, Shuang-Xi Gu, Yong-Shou Chen, Xu-Dong Gao, Yi-Xin Ren, Jian-Chao Chen, Yin-Ying Lu, Heng Zhang, Shuang Cao. <p>Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma</p>. Drug Design, Development and Therapy 2020, Volume 14 , 1779-1798.
    62. Abdulhameed Al-Ghabkari, Maneka A. Perinpanayagam, Aru Narendran. Inhibition of PI3K/mTOR Pathways with GDC-0980 in Pediatric Leukemia: Impact on Abnormal FLT-3 Activity and Cooperation with Intracellular Signaling Targets. Current Cancer Drug Targets 2019, 19 (10) , 828-837.
    63. Monica M. Kangussu-Marcolino, Gretchen M. Ehrenkaufer, Emily Chen, Anjan Debnath, Upinder Singh. Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia. International Journal for Parasitology: Drugs and Drug Resistance 2019, 11 , 80-94.
    64. Shengquan Hu, Zhichang Zhao, Hong Yan. Discovery and optimization of 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives as mTORC1/mTORC2 dual inhibitors. Bioorganic Chemistry 2019, 92 , 103232.
    65. Yong Yin, Yang Zhou, Shao Sha, Xun Wu, She-Feng Wang, Fang Qiao, Zhong-Cheng Song, Hai-Liang Zhu. Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3Kα. Bioorganic Chemistry 2019, 92 , 103238.
    66. Yuan-Yuan Hei, San-Qi Zhang, Yifan Feng, Jin Wang, Weiming Duan, Hao Zhang, Shuai Mao, Haopeng Sun, Minhang Xin. Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors. Bioorganic & Medicinal Chemistry 2019, 27 (20) , 114930.
    67. Lide Yu, Qinqin Wang, Caolin Wang, Binliang Zhang, Zunhua Yang, Yuanying Fang, Wufu Zhu, Pengwu Zheng. Design, Synthesis, and Biological Evaluation of Novel Thienopyrimidine Derivatives as PI3Kα Inhibitors. Molecules 2019, 24 (19) , 3422.
    68. Guoyi Yan, Chunlan Pu, Suke Lan, Xinxin Zhong, Meng Zhou, Xueyan Hou, Jie Yang, Huifang Shan, Lifeng Zhao, Rui Li. Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors. European Journal of Medicinal Chemistry 2019, 178 , 667-686.
    69. Eslam M.H. Ali, Mohammed S. Abdel-Maksoud, Chang-Hyun Oh. Thieno[2,3-d]pyrimidine as a promising scaffold in medicinal chemistry: Recent advances. Bioorganic & Medicinal Chemistry 2019, 27 (7) , 1159-1194.
    70. Shuying Liu, Shunqiang Li, Bailiang Wang, Wenbin Liu, Mihai Gagea, Huiqin Chen, Joohyuk Sohn, Napa Parinyanitikul, Tina Primeau, Kim-Anh Do, George F. Vande Woude, John Mendelsohn, Naoto T. Ueno, Gordon B. Mills, Debu Tripathy, Ana M. Gonzalez-Angulo. Cooperative Effect of Oncogenic MET and PIK3CA in an HGF-Dominant Environment in Breast Cancer. Molecular Cancer Therapeutics 2019, 18 (2) , 399-412.
    71. Michael McKenna, Sarah McGarrigle, Graham P. Pidgeon. The next generation of PI3K-Akt-mTOR pathway inhibitors in breast cancer cohorts. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2018, 1870 (2) , 185-197.
    72. Hui-Yan Wang, Ying Shen, Hao Zhang, Yuan-Yuan Hei, Hong-Yi Zhao, Minhang Xin, She-Min Lu, San-Qi Zhang. Discovery of 2-(aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6- Substituted Triazine as PI3K and BRAF Dual Inhibitor. Future Medicinal Chemistry 2018, 10 (20) , 2445-2455.
    73. John E. Burke. Structural Basis for Regulation of Phosphoinositide Kinases and Their Involvement in Human Disease. Molecular Cell 2018, 71 (5) , 653-673.
    74. Fu-Dan Dong, Dan-Dan Liu, Cheng-Long Deng, Xiao-chun Qin, Kai Chen, Jian Wang, Hong-Rui Song, Huai-Wei Ding. Design, synthesis and biological evaluation of novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold derivatives as PI3Kα inhibitors. Bioorganic & Medicinal Chemistry 2018, 26 (14) , 3982-3991.
    75. Frederick A. Partridge, Ruth Forman, Nicky J. Willis, Carole J. R. Bataille, Emma A. Murphy, Anwen E. Brown, Narinder Heyer-Chauhan, Bruno Marinič, Daniel J. C. Sowood, Graham M. Wynne, Kathryn J. Else, Angela J. Russell, David B. Sattelle, . 2,4-Diaminothieno[3,2-d]pyrimidines, a new class of anthelmintic with activity against adult and egg stages of whipworm. PLOS Neglected Tropical Diseases 2018, 12 (7) , e0006487.
    76. Remya Ramesh, Swapnil Sonawane, D. Srinivasa Reddy, Rakeshwar Bandichhor. Protecting‐Group‐Free Synthesis of Drugs and Pharmaceuticals. 2018, 155-181.
    77. Bingbing Zhao, Fei Lei, Caolin Wang, Binliang Zhang, Zunhua Yang, Wei Li, Wufu Zhu, Shan Xu. Design, Synthesis and Biological Evaluation of Novel Phenylsulfonylurea Derivatives as PI3K/mTOR Dual Inhibitors. Molecules 2018, 23 (7) , 1553.
    78. Ronald Nelson, Taylor Schronce, Yue Huang, Alanoud Albugami, George Kulik, Mark Welker. Synthesis and PI 3-Kinase Inhibition Activity of Some Novel 2,4,6-Trisubstituted 1,3,5-Triazines. Molecules 2018, 23 (7) , 1628.
    79. Emily Wright, Ronald Nelson, Yelena Karpova, George Kulik, Mark Welker. Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines. Molecules 2018, 23 (7) , 1675.
    80. Ricardo L. B. Costa, Hyo Sook Han, William J. Gradishar. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Research and Treatment 2018, 169 (3) , 397-406.
    81. S. Ganesamoorthy, M. Muthu Tamizh, K. Shanmugasundaram, R. Karvembu. A sustainable heterogenized palladium catalyst for Suzuki-Miyaura cross coupling reaction of azaheteroaryl halides in aqueous media. Journal of Organometallic Chemistry 2018, 862 , 76-85.
    82. Rebecca Mitchell, Lisa E M Hopcroft, Pablo Baquero, Elaine K Allan, Kay Hewit, Daniel James, Graham Hamilton, Arunima Mukhopadhyay, Jim O’Prey, Alan Hair, Junia V Melo, Edmond Chan, Kevin M Ryan, Véronique Maguer-Satta, Brian J Druker, Richard E Clark, Subir Mitra, Pawel Herzyk, Franck E Nicolini, Paolo Salomoni, Emma Shanks, Bruno Calabretta, Tessa L Holyoake, G Vignir Helgason. Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition. JNCI: Journal of the National Cancer Institute 2018, 110 (5) , 467-478.
    83. Michael D. Bright, Paul A. Clarke, Paul Workman, Faith E. Davies. Oncogenic RAC1 and NRAS drive resistance to endoplasmic reticulum stress through MEK/ERK signalling. Cellular Signalling 2018, 44 , 127-137.
    84. Posa Venkata Sri Ramya, Sowjanya Thatikonda, Srinivas Angapelly, Bathini Nagendra Babu, Vegi Ganga Modi Naidu, Ahmed Kamal. Synthesis and Biological Evaluation of Thieno[2, 3‐ d ]pyrimidine‐amides as Potential Anticancer Agents. ChemistrySelect 2018, 3 (11) , 3101-3106.
    85. . 2‐Aminopyrimidines. 2018, 237-283.
    86. Xiaodong Ma, Xiaoqing Lv, Jiankang Zhang. Exploiting polypharmacology for improving therapeutic outcome of kinase inhibitors (KIs): An update of recent medicinal chemistry efforts. European Journal of Medicinal Chemistry 2018, 143 , 449-463.
    87. Supreet Gaonkar, Mohammed Azharuddin Savanur, Manjunath G. Sunagar, Bijesh Puthusseri, Narahari Deshapande, Afra A. Nadaf, Imtiyaz Ahmed M. Khazi. Exploring the potential of newly synthesized 4-methyl-6-morpholino-pyrimidine derivatives as antiproliferative agents. New Journal of Chemistry 2018, 42 (4) , 2790-2803.
    88. Hua-fu Zhao, Jing Wang, Wei Shao, Chang-peng Wu, Zhong-ping Chen, Shing-shun Tony To, Wei-ping Li. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Molecular Cancer 2017, 16 (1)
    89. Luca Costantino, Daniela Barlocco. Designing Approaches to Multitarget Drugs. 2017, 161-205.
    90. Marta Érica Saidel, Karen C. dos Santos, Luís F.P. Nagano, Carlos Alberto Montanari, Andrei Leitão. Novel anti-prostate cancer scaffold identified by the combination of in silico and cell-based assays targeting the PI3K-AKT-mTOR pathway. Bioorganic & Medicinal Chemistry Letters 2017, 27 (17) , 4001-4006.
    91. Peng-Cheng Diao, Qiu Li, Meng-Jin Hu, Yu-Feng Ma, Wen-Wei You, Kwon Ho Hong, Pei-Liang Zhao. Synthesis and biological evaluation of novel indole-pyrimidine hybrids bearing morpholine and thiomorpholine moieties. European Journal of Medicinal Chemistry 2017, 134 , 110-118.
    92. Jiankang Zhang, Xiaoqing Lv, Xiaodong Ma, Yongzhou Hu. Discovery of a series of N -(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as PI3K/mTOR dual inhibitors. European Journal of Medicinal Chemistry 2017, 127 , 509-520.
    93. Yu Liu, Wen-zhu Wan, Yan Li, Guan-lian Zhou, Xin-guang Liu. Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents. Oncotarget 2017, 8 (4) , 7181-7200.
    94. Marjorie G. Zauderer. Standard Chemotherapy Options and Clinical Trials of Novel Agents for Mesothelioma. 2017, 313-345.
    95. Keiichi Ito. Forthcoming Drugs for Metastatic Renal Cell Carcinoma Therapy. 2017, 333-349.
    96. Sergio Rey, Luana Schito, Marianne Koritzinsky, Bradly G. Wouters. Molecular targeting of hypoxia in radiotherapy. Advanced Drug Delivery Reviews 2017, 109 , 45-62.
    97. Patricia Mucci LoRusso. Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors. Journal of Clinical Oncology 2016, 34 (31) , 3803-3815.
    98. Jinsong Han, Ying Chen, Chao Yang, Ting Liu, Mingping Wang, Haojie Xu, Ling Zhang, Canhui Zheng, Yunlong Song, Ju Zhu. Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor. European Journal of Medicinal Chemistry 2016, 122 , 684-701.
    99. Sara S. Franco, Karolina Szczesna, Maria S. Iliou, Mohammed Al-Qahtani, Ali Mobasheri, Julianna Kobolák, András Dinnyés. In vitro models of cancer stem cells and clinical applications. BMC Cancer 2016, 16 (S2)
    100. Hend N. Hafez, Abdel-Rhman B. A. El-Gazzar, Magdi E. A. Zaki. Simple approach to thieno[3,2-d]pyrimidines as new scaffolds of antimicrobial activities. Acta Pharmaceutica 2016, 66 (3) , 331-351.
    Load all citations

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect