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Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy
Journal of Medicinal Chemistry  (IF7.446),  Pub Date : 2021-11-15, DOI: 10.1021/acs.jmedchem.1c01308
Zhuqing Zhang, Zuhao Guo, Xiaowei Xu, Danyan Cao, Hong Yang, Yanlian Li, Qiongyu Shi, Zhiyan Du, Xiaobin Guo, Xin Wang, Danqi Chen, Ying Zhang, Lin Chen, Kaixin Zhou, Jian Li, Meiyu Geng, Xun Huang, Bing Xiong

CARM1 is a protein arginine methyltransferase and acts as a transcriptional coactivator regulating multiple biological processes. Aberrant expression of CARM1 has been related to the progression of multiple types of cancers, and therefore CARM1 was considered as a promising drug target. In the present work, we report the structure-based discovery of a series of N1-(3-(pyrimidin-2-yl)benzyl)ethane-1,2-diamines as potent CARM1 inhibitors, in which compound 43 displays high potency and selectivity. With the advantage of excellent tissue distribution, compound 43 demonstrated good in vivo efficacy for solid tumors. Furthermore, from the detailed immuno-oncology study with MC38 C57BL/6J xenograft model, we confirmed that this chemical probe 43 has profound effects in tumor immunity, which paves the way for future studies on the modulation of arginine post-translational modification that could be utilized in solid tumor treatment and cancer immunotherapy.