Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders.

ABSTRACT: CARM1 is amplified or overexpressed in many cancer types, and its overexpression correlates with poor prognosis. Potent small-molecule inhibitors for CARM1 have been developed, but the cellular efficacy of the CARM1 inhibitors is limited. We herein report the development of the proteolysis targeting chimera (PROTAC) for CARM1, which contains a CARM1 ligand TP-064, a linker, and a VHL E3 ligase ligand. Compound 3b elicited potent cellular degradation activity (DC₅₀ = 8 nM and D_max > 95%) in a few hours. Compound 3b degraded CARM1 in VHL- and proteasome-dependent manner and was highly selective for CARM1 over other protein arginine methyltransferases. CARM1 degradation by 3b resulted in potent downregulation of CARM1 substrate methylation and

SUBMITTER: Xie H 

PROVIDER: S-EPMC10775954 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature