Orsi Douglas L, Lazarski Kiel E, Improgo Reina, Agafonov R V, Ahn Jae Young, Baddour Joelle, Cassidy Katelyn, Chaturvedi Prasoon, Cole Kyle S, Deibler Richard W, Elam W Austin, Fitzgerald Mark E, Garza Victoria J, Good Andrew, Hulton Christopher H, Isasa Marta, Jackson Katrina L, Li Ping, Liang Yanke, Michael Ryan E, O'Shea Morgan Welzel, Moustakim Moses, Perino Samantha, Rahman Fazlur, Schnaderbeck Matthew J, Stone Nicholas P, Tillotson Bonnie, Veits Gesine K, Vogelaar Abigail, Yap Jeremy L, Yu Robert T, Huang Hongwei, Henderson James A
C4 Therapeutics 490 Arsenal Way, Suite 120 Watertown MA 02472 USA
RSC Med Chem. 2025 Aug 13. doi: 10.1039/d5md00337g.
Point mutations and chromosomal fusions of the Rearranged During Transfection (RET) transmembrane receptor tyrosine kinase cause constitutive substrate-free activation, driving numerous human cancers. RET-selective kinase inhibitors (selpercatinib, pralsetinib) are in current clinical use for RET-driven tumors. However, the emergence of resistance mutations, such as those at the solvent-front G810 residue, results in reduced efficacy. We sought to exploit the event-driven pharmacology of targeted protein degradation to achieve pan-mutant activity against RET-driven cancers with a single selective RET degrader, while utilizing non-phthalimide cereblon (CRBN) ligands to discover orally bioavailable heterobifunctional degraders. Here we describe the medicinal chemistry efforts that led to compound 20, an orally bioavailable, brain-penetrant, pan-mutant and pan-fusion RET heterobifunctional degrader.
转染期间重排（RET）跨膜受体酪氨酸激酶的点突变和染色体融合会导致组成性无底物激活，从而引发多种人类癌症。RET选择性激酶抑制剂（塞尔帕替尼、普拉替尼）目前在临床上用于治疗RET驱动的肿瘤。然而，耐药性突变的出现，如溶剂前沿G810残基处的突变，会导致疗效降低。我们试图利用靶向蛋白质降解的事件驱动药理学，通过单一选择性RET降解剂实现对RET驱动癌症的全突变活性，同时利用非邻苯二甲酰亚胺类脑啡肽酶（CRBN）配体发现口服生物可利用的异双功能降解剂。在此，我们描述了导致化合物20的药物化学研究工作，化合物20是一种口服生物可利用、可穿透血脑屏障、全突变和全融合的RET异双功能降解剂。
