Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader
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.
Authors
- Douglas L. Orsi (ORCID: https://orcid.org/0000-0001-6731-5494)
- Richard W. Deibler (ORCID: https://orcid.org/0000-0003-2226-8190)
- Reina Improgo
- Nicholas P. Stone (ORCID: https://orcid.org/0000-0002-5869-0329)
- Yanke Liang (ORCID: https://orcid.org/0009-0006-5539-9946)
- Mark E. Fitzgerald (ORCID: https://orcid.org/0009-0001-9449-7892)
- Marta Isasa (ORCID: https://orcid.org/0009-0005-6865-9500)
- Prasoon Chaturvedi (ORCID: https://orcid.org/0009-0002-4322-2933)
- Abigail Vogelaar (ORCID: https://orcid.org/0000-0002-6599-0311)
- Joelle Baddour (ORCID: https://orcid.org/0009-0007-6654-0383)
- Jeremy L. Yap
- Ryan E. Michael
- W. Austin Elam
- Gesine K. Veits
- Moses Moustakim (ORCID: https://orcid.org/0000-0002-5006-5684)
- Katrina L. Jackson
- Katelyn Cassidy (ORCID: https://orcid.org/0000-0002-4487-0011)
- J. Ahn
- Kyle S. Cole
- Robert Yu
- Morgan Welzel O’Shea
- Matthew Schnaderbeck
- Bonnie Tillotson
- Victoria Garza
- Fazlur Rahman
- Roman V. Agafonov (ORCID: https://orcid.org/0000-0002-7765-899X)
- Christopher H. Hulton
- Ping Li (ORCID: https://orcid.org/0000-0001-8285-8921)
- Hongwei Huang (ORCID: https://orcid.org/0000-0001-8269-4461)
- Andrew C. Good (ORCID: https://orcid.org/0009-0001-9910-6475)
- Samantha Perino
- J. M. Henderson
- Kiel E. Lazarski
Institutions
- C4 Therapeutics (United States) (US)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5md00337g
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81