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

• Published in: Journal of chemical information and modeling Vol. 62; no. 3; pp. 692 - 702
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.02.2022
• Subjects: Anticancer properties; Arginine; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Pharmaceutical Modeling; Protein Binding; Protein-Arginine N-Methyltransferases - chemistry; Proteins
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.1c01100

CARM1 (coactivator-associated arginine methyltransferase 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 μM) 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.