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TrkC-Targeted Kinase Inhibitors And PROTACs

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Mol. Pharmaceutics 2019, 16, 10, 4313-4318
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    TrkC-Targeted Kinase Inhibitors And PROTACs
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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2019, 16, 10, 4313–4318
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    https://doi.org/10.1021/acs.molpharmaceut.9b00673
    Published September 12, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    A small molecule motif (IY–IY), which binds the tropomyosin receptor kinase C (TrkC), was used to deliver the promiscuous kinase inhibitor (KI) dasatinib into breast cancer. Conjugates with noncleavable (1) and cleavable (2) linkers were compared in cellular assays and shown to have more impact on the cell viabilities of TrkC+ breast cancer cells over TrkC– epithelial cells. The IY–IY fragment was also used to recruit the E3 ligase cereblon, giving a potent proteolysis targeting chimeric (PROTAC) for TrkC degradation in metastatic breast cancer cells.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.9b00673.

    • Synthesis and characterization of intermediates and key compounds 1–4; procedures for biological assays (cytotoxicity assay, wound healing assay, Western blot, protein degradation); supplementary figures (compound stabilities, wound healing, cytotoxicity, protein degradation) (PDF)

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    Cited By

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    This article is cited by 26 publications.

    1. Liqun Chen, Yanke Chen, Chunyan Zhang, Bingyang Jiao, Sheng Liang, Qiong Tan, Hongyu Chai, Weihua Yu, Yongzheng Qian, Hui Yang, Wuyi Yao, Jianguo Yu, Ying Luo, Michael Plewe, Jialiang Wang, Xiao-Ran Han, Jing Liu. Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders. Journal of Medicinal Chemistry 2020, 63 (23) , 14562-14575. https://doi.org/10.1021/acs.jmedchem.0c01342
    2. Shareef Shaik, Prasanna Kumar Reddy Gayam, Manish Chaudhary, Gurvinder Singh, Aravinda Pai. Advances in designing ternary complexes: Integrating in-silico and biochemical methods for PROTAC optimisation in target protein degradation. Bioorganic Chemistry 2024, 2016 , 107868. https://doi.org/10.1016/j.bioorg.2024.107868
    3. Zhenjie Wang, Siyao Che, Zhiqiang Yu. PROTAC: Novel degradable approach for different targets to treat breast cancer. European Journal of Pharmaceutical Sciences 2024, 198 , 106793. https://doi.org/10.1016/j.ejps.2024.106793
    4. Alastair C. Keen, Manuela Jörg, Michelle L. Halls. The application of targeted protein degradation technologies to G protein‐coupled receptors. British Journal of Pharmacology 2024, 181 (14) , 2351-2358. https://doi.org/10.1111/bph.16079
    5. Shuang Xiang, Xiaoyun Lu. Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib. Acta Pharmaceutica Sinica B 2024, 14 (2) , 517-532. https://doi.org/10.1016/j.apsb.2023.11.010
    6. Abhishek Wahi, Hemant R. Jadhav, Shikha Thakur, Sushma Dev, Priyanka Mohanty, Priti Jain. Structural Considerations and Chemistry of PROTACs. 2024, 39-66. https://doi.org/10.1007/978-981-97-5077-1_3
    7. Siyu Chen, Jingliang Cui, Haiyan Chen, Bo Yu, Sihui Long. Recent progress in degradation of membrane proteins by PROTACs and alternative targeted protein degradation techniques. European Journal of Medicinal Chemistry 2023, 262 , 115911. https://doi.org/10.1016/j.ejmech.2023.115911
    8. Chao Wang, Yujing Zhang, Shanbo Yang, Dongming Xing. Recent advances of PROTACs technology in neurodegenerative diseases. Arabian Journal of Chemistry 2023, 16 (9) , 105015. https://doi.org/10.1016/j.arabjc.2023.105015
    9. Gaidaa M. Dogheim, Mohamed T. Amralla. Proteolysis Targeting Chimera (PROTAC) as a promising novel therapeutic modality for the treatment of triple‐negative breast cancer (TNBC). Drug Development Research 2023, 84 (4) , 629-653. https://doi.org/10.1002/ddr.22055
    10. Jin Li, Xinxin Chen, Aiping Lu, Chao Liang. Targeted protein degradation in cancers: Orthodox PROTACs and beyond. The Innovation 2023, 4 (3) , 100413. https://doi.org/10.1016/j.xinn.2023.100413
    11. Hong‐Yi Zhao, Minhang Xin, San‐Qi Zhang. Progress of small molecules for targeted protein degradation: PROTACs and other technologies. Drug Development Research 2023, 84 (2) , 337-394. https://doi.org/10.1002/ddr.22026
    12. Marcin Cieślak, Marta Słowianek. Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges?. Pharmaceutics 2023, 15 (3) , 812. https://doi.org/10.3390/pharmaceutics15030812
    13. Haleema Ahmad, Bushra Zia, Hashir Husain, Afzal Husain. Recent Advances in PROTAC-Based Antiviral Strategies. Vaccines 2023, 11 (2) , 270. https://doi.org/10.3390/vaccines11020270
    14. Ming He, Chaoguo Cao, Zhihao Ni, Yongbo Liu, Peilu Song, Shuang Hao, Yuna He, Xiuyun Sun, Yu Rao. PROTACs: great opportunities for academia and industry (an update from 2020 to 2021). Signal Transduction and Targeted Therapy 2022, 7 (1) https://doi.org/10.1038/s41392-022-00999-9
    15. Xinyi Li, Wenchen Pu, Qingquan Zheng, Min Ai, Song Chen, Yong Peng. Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Molecular Cancer 2022, 21 (1) https://doi.org/10.1186/s12943-021-01434-3
    16. André T. S. Vicente, Jorge A. R. Salvador. MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment. International Journal of Molecular Sciences 2022, 23 (19) , 11068. https://doi.org/10.3390/ijms231911068
    17. Wu Du. Targeted Protein Degradation by Proteolysis Targeting Chimeras. 2022, 225-271. https://doi.org/10.1002/9781119627784.ch11
    18. Xin Han, Wenyi Wei, Yi Sun. PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective. Acta Materia Medica 2022, 1 (2) https://doi.org/10.15212/AMM-2022-0010
    19. Hyoung Kyu Kim, Jung Eun Seol, Sang Woo Ahn, Seungje Jeon, Chul-Seung Park, Jin Han. Cereblon: promise and challenges for combating human diseases. Pflügers Archiv - European Journal of Physiology 2021, 473 (11) , 1695-1711. https://doi.org/10.1007/s00424-021-02624-0
    20. Aleša Bricelj, Christian Steinebach, Robert Kuchta, Michael Gütschow, Izidor Sosič. E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points. Frontiers in Chemistry 2021, 9 https://doi.org/10.3389/fchem.2021.707317
    21. Zhiwen Qi, Guliang Yang, Tao Deng, Jianmin Wang, Hao Zhou, Sergey A. Popov, Elvira E. Shults, Chengzhang Wang. Design and linkage optimization of ursane-thalidomide-based PROTACs and identification of their targeted-degradation properties to MDM2 protein. Bioorganic Chemistry 2021, 111 , 104901. https://doi.org/10.1016/j.bioorg.2021.104901
    22. Tingting Jiang, Guan Wang, Yao Liu, Lu Feng, Meng Wang, Jie Liu, Yi Chen, Liang Ouyang. Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers. Acta Pharmaceutica Sinica B 2021, 11 (2) , 355-372. https://doi.org/10.1016/j.apsb.2020.05.004
    23. Shenxin Zeng, Wenhai Huang, Xiaoliang Zheng, Liyan cheng, Zhimin Zhang, Jian Wang, Zhengrong Shen. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges. European Journal of Medicinal Chemistry 2021, 210 , 112981. https://doi.org/10.1016/j.ejmech.2020.112981
    24. M. Maneiro, E. De Vita, D. Conole, C.S. Kounde, Q. Zhang, E.W. Tate. PROTACs, molecular glues and bifunctionals from bench to bedside: Unlocking the clinical potential of catalytic drugs. 2021, 67-190. https://doi.org/10.1016/bs.pmch.2021.01.002
    25. Anthony Feral, Guillaume Laconde, Muriel Amblard, Nicolas Masurier. PROteolysis TArgetting Chimeras (PROTACs) Strategy Applied to Kinases: Recent Advances. Advanced Therapeutics 2020, 3 (11) https://doi.org/10.1002/adtp.202000148
    26. Rati Verma, Dane Mohl, Raymond J. Deshaies. Harnessing the Power of Proteolysis for Targeted Protein Inactivation. Molecular Cell 2020, 77 (3) , 446-460. https://doi.org/10.1016/j.molcel.2020.01.010
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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2019, 16, 10, 4313–4318
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.9b00673
    Published September 12, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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