European Journal of Medicinal Chemistry p. 317 - 333 (2019)
Update date:2022-08-15
Topics:
Shao, Jingwei
Zhu, Kongkai
Du, Daohai
Zhang, Yuanyuan
Tao, Hongrui
Chen, Zhifeng
Jiang, Hualiang
Chen, Kaixian
Luo, Cheng
Duan, Wenhu
Protein arginine methyltransferases 5 (PRMT5) represents an attractive drug target in epigenetic field for the treatment of leukemia and lymphoma. Here, a series of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amide derivatives targeting PRMT5 were designed with structure-based approach and synthesized. Among them, compound 46 showed potent and selective PRMT5 inhibition activity with an IC50 of 8.5 nM, which was approximately equivalent with the phase I clinical trial PRMT5 inhibitor GSK-3326595 (IC50 = 5.5 nM). Compound 46 also displayed pronounced anti-proliferative activity in MV4-11 cells (GI50 = 18 nM) and antitumor activity in MV4-11 mouse xenografts model. This molecule can serve as an excellent tool compound for probing the biological function of PRMT5.
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