Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader

  • RSC Med Chem. 2025 Aug 13. doi: 10.1039/d5md00337g.
Douglas L Orsi  1 ,  Kiel E Lazarski  1 ,  Reina Improgo  1 ,  R V Agafonov  1 ,  Jae Young Ahn  1 ,  Joelle Baddour  1 ,  Katelyn Cassidy  1 ,  Prasoon Chaturvedi  1 ,  Kyle S Cole  1 ,  Richard W Deibler  1 ,  W Austin Elam  1 ,  Mark E Fitzgerald  1 ,  Victoria J Garza  1 ,  Andrew Good  1 ,  Christopher H Hulton  1 ,  Marta Isasa  1 ,  Katrina L Jackson  1 ,  Ping Li  1 ,  Yanke Liang  1 ,  Ryan E Michael  1 ,  Morgan Welzel O'Shea  1 ,  Moses Moustakim  1 ,  Samantha Perino  1 ,  Fazlur Rahman  1 ,  Matthew J Schnaderbeck  1 ,  Nicholas P Stone  1 ,  Bonnie Tillotson  1 ,  Gesine K Veits  1 ,  Abigail Vogelaar  1 ,  Jeremy L Yap  1 ,  Robert T Yu  1 ,  Hongwei Huang  1 ,  James A Henderson  1
Affiliations
  • 1. C4 Therapeutics 490 Arsenal Way, Suite 120 Watertown MA 02472 USA [email protected].
PMID: 40823490 DOI: 10.1039/d5md00337g
Abstract

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.

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