Design, synthesis and activity evaluation of protein arginine methyltransferase 5 inhibitor
10.16438/j.0513-4870.2020-0568
- VernacularTitle:蛋白质精氨酸甲基转移酶5抑制剂的设计、合成及活性评价
- Author:
Kang-le ZHU
1
,
2
;
Ya-zhou WANG
3
;
Qi-dong YOU
1
Author Information
1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
2. Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 210000, China
3. Nanjing Sanhome Pharmaceutical Co., Ltd., Nanjing 210000, China
- Publication Type:Research Article
- Keywords:
PRMT5;
structural optimization;
cancer;
GSK332659
- From:
Acta Pharmaceutica Sinica
2020;55(8):1859-1871
- CountryChina
- Language:Chinese
-
Abstract:
Protein arginine methyltransferase 5 (PRMT5) is an important type II human methyltransferase. It catalyzes the symmetrical double-methylation of many histones and non-histones, and it is highly expressed in many kinds of tumors. PRMT5 has been proven to be a potential new target for cancer treatment. Based on the reported crystal complex of EPZ015666 with PRMT5, a series of new compounds was designed using GSK3326595 (EPZ015938) as the lead compound and using the conformational restriction approach. We found that compounds B8 and the C series of derivatives displayed enzyme inhibitory activity comparable to that of GSK3326595. Compounds C3 and C4 showed poor permeability in Caco-2 cells, and that might be one of the reasons for their poor anti-proliferative activity against Z-138 cells. These data provide insights for further structural optimization.
