1. Academic Validation
  2. Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader

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

Affiliation

  • 1 C4 Therapeutics 490 Arsenal Way, Suite 120 Watertown MA 02472 USA jhenderson@c4therapeutics.com.
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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