ARTICLE | Distillery Therapeutics
A SMARCA2-degrading PROTAC for SMARCA4-deficient cancer
December 7, 2022 8:49 PM UTC
An orally bioavailable proteolysis targeting chimera (PROTAC) that degrades the chromatin remodeling enzyme SMARCA2 by recruiting the E3 ubiquitin ligase vHL could help treat cancers deficient in the SMARCA2 paralog SMARCA4 via synthetic lethality.
Structure-guided optimization resulted in a quinazolinone-based SMARCA2 ligand that was coupled to an optimized linker and vHL-recruiting domain, yielding a compound that degraded SMARCA2 with an EC50 of 7nM and had an oral bioavailability of 22% in mice and selectively degraded SMARCA2 over SMARCA4 in blood from healthy donors...