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

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 com

SUBMITTER: Orsi DL 

PROVIDER: S-EPMC12352630 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature