Biological evaluation of 2-methylpyrimidine derivatives as active pan Bcr-Abl inhibitors  

作　　者：ZOU DingBiao QIU YaTao TU ZhengChao LIAO ChenZhong LUO JinFeng MENG QingQing YAO RiSheng LI Zheng JIANG Sheng 

机构地区：[1]Laboratory of Medicinal Chemistry,Guangzhou Institute of Biomedicine and Health,Chinese Academy of Sciences [2]School of Medical Engineering,Hefei University of Technology [3]Department of Radiology,the Methodist Hospital Research Institute

出　　处：《Science China Chemistry》2014年第6期823-832,共10页中国科学（化学英文版）

基　　金：supported by the National Natural Science Foundation of China(21172220);the National Basic Research Program of China(2009CB940900)

摘　　要：We designed a series of 2-methylpyrimidine derivatives as new BCR-ABL inhibitors using scaffold-hopping strategy.These synthetic compounds exhibited significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I mutant.Compound 7u showed very potent kinase inhibitory activities against Bcr-Abl WT,Bcr-Abl E255K,Bcr-Abl Q252H,Bcr-Abl G250E and Bcr-Abl T315I,with IC50 values of 0.13 nM,0.17 nM,0.24 nM,0.19 nM and 0.65μM,respectively.This compound also displayed anti-proliferation activity against K562 cell line with an IC50 value of 1.1 nM,thus representing a new lead for further optimization.We designed a series of 2-methylpyrimidine derivatives as new BCR-ABL inhibitors using scaffold-hopping strategy.These synthetic compounds exhibited significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I mutant.Compound 7u showed very potent kinase inhibitory activities against Bcr-Abl WT,Bcr-Abl E255K,Bcr-Abl Q252H,Bcr-Abl G250E and Bcr-Abl T315I,with IC50 values of 0.13 nM,0.17 nM,0.24 nM,0.19 nM and 0.65μM,respectively.This compound also displayed anti-proliferation activity against K562 cell line with an IC50 value of 1.1 nM,thus representing a new lead for further optimization.

关 键 词：chronic myeloid leukemia（CML） anticancer agents BCR-ABL imatinib resistance 

分 类 号：TQ460.1[化学工程—制药化工]