Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders,Journal of Medicinal Chemistry

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Development of Potent and Selective Coactivator-Associated Arginine Methyltransferase 1 (CARM1) Degraders
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-13 , DOI: 10.1021/acs.jmedchem.3c00982
Haibo Xie ₁ , Megan S Bacabac ₂ , Min Ma ₁ , Eui-Jun Kim ₂ , Yidan Wang ₂ , Wenxin Wu ₃ , Lingjun Li _{1,

3} , Wei Xu ₂ , Weiping Tang _{1,

3}

Affiliation

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 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.

中文翻译：

强效选择性共激活剂相关精氨酸甲基转移酶 1 (CARM1) 降解剂的开发

CARM1 在许多癌症类型中扩增或过度表达，其过度表达与不良预后相关。 CARM1 的有效小分子抑制剂已经开发出来，但 CARM1 抑制剂的细胞功效有限。我们在此报告了 CARM1 的蛋白水解靶向嵌合体 (PROTAC) 的开发，该嵌合体包含 CARM1 配体 TP-064、接头和 VHL E3 连接酶配体。化合物3b在几小时内引发了有效的细胞降解活性（DC ₅₀ = 8 nM 且D _max > 95%）。化合物3b以 VHL 和蛋白酶体依赖性方式降解 CARM1，并且对 CARM1 的选择性高于其他蛋白质精氨酸甲基转移酶。在基于细胞的检测中， 3b降解 CARM1 导致 CARM1 底物甲基化的有效下调并抑制癌细胞迁移。因此，CARM1 PROTAC 可用于检测 CARM1 的细胞功能，并有可能开发为针对 CARM1 驱动的癌症的治疗剂。

更新日期：2023-09-13

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