甲基转移酶
生物化学
化学
蛋白质精氨酸甲基转移酶5
蛋白酶体
甲基化
细胞生长
精氨酸
泛素
生物
氨基酸
基因
作者
Haibo Xie,Megan S. Bacabac,Min Ma,Eui‐Jun Kim,Yidan Wang,Wenxin Wu,Lingjun Li,Wei Xu,Weiping Tang
标识
DOI:10.1021/acs.jmedchem.3c00982
摘要
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.
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