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

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 Dmax > 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 inhibition
of cancer cell migration in cell-based assays. Thus, CARM1 PROTACs
can be used to interrogate CARM1’s cellular functions and potentially
be developed as therapeutic agents for targeting CARM1-driven cancers.