Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type I Protein Arginine Methyltransferases

作者：Li, Xiao; Zhang, Lun; Xu, Jing; Liu, Chenyu; Zhang, Xiaojian; Abdelmoneim, Amr Abbas; Zhang, Qian; Ke, Jiaqi; Zhang, Yingnan; Wang, Lei; Yang, Fan; Luo, Cheng; Jin, Jia^*; Ye, Fei^*

来源：Journal of Chemical Information and Modeling, 2022, 62(3): 692-702.

DOI：10.1021/acs.jcim.1c01100

• CARM1
• METHYLATION
• INSIGHTS
• PAINS

CARM1 (coactivator-associated arginine methyl-transferase 1), which belongs to type I PRMTs (protein arginine methyltransferases), is a potential therapeutic target for treatment of multiple cancers. In this study, we first identified several hit compounds against CARM1 by structure-based virtual screening (IC50 = 35.51 +/- 6.68 to 68.70 +/- 8.12 mu M) and then carried out chemical structural optimizations, leading to six compounds with significantly improved activities targeting CARM1 (IC50 = 18 +/- 2 to 107 +/- 6 nM). As a compound with an ethylenediamino motif, the most potent inhibitor, ZL-28-6, also exhibited potent inhibition against other type I PRMTs. Compared to the type I PRMT inhibitor from our previous work (DCPR049_12), ZL-28-6 showed increased potency against CARM1 and decreased activity against other type I PRMTs. Moreover, ZL-28-6 showed better antiproliferation activities toward a series of solid tumor cells than DCPR049_12, indicating its broad spectrum of anticancer activity. In addition, cellular thermal shift and Western blot assays validated that ZL-28-6 could target CARM1 in cells. Taken together, the inhibitor we identified could serve as a potent probe for studying CARM1's biological functions and shed light on the future design of novel CARM1 inhibitors with stronger activities and selectivities.

• 单位
  中国科学院研究生院