posted on 2021-11-16, 06:44authored byZhuqing 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.