title: Hybrid pyrimidine alkynyls inhibit the clinically resistance related Bcr-Abl(T315I) mutant.
abstract: A series of pyrimidine alkynyl derivatives were designed and synthesized as new Bcr-Abl inhibitors by hybriding the structural moieties from GNF-7, ponatinib and nilotinib. One of the most potent compounds 4e strongly suppresses Bcr-Abl(WT) and Bcr-Abl(T315I) kinase with IC50 values of 5.0 and 9.0 nM, and inhibits the proliferation of K562 and murine Ba/F3 cells ectopically expressing Bcr-Abl(T315I) cells with IC50 values of 2 and 50 nM, respectively. It also displays good pharmacokinetics properties with an oral bioavailability of 35.3% and T(1/2) value of 48.7 h, and demonstrates significantly suppression on tumor growth in xenografted mice of K562 and Ba/F3 cells expressing Bcr-Abl(T315I). These inhibitors may serve as lead compounds for further developing new anticancer drugs overcoming the clinically acquired resistance against current Bcr-Abl inhibitors.
authors.affiliation: Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China. Electronic address: lu_xiaoyun@gibh.ac.cn.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.affiliation: Biotechnological Institute of Chinese Materia Medica and Department of Pharmacology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.affiliation: Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Pan
authors.affiliation: Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Luo
authors.affiliation: Biotechnological Institute of Chinese Materia Medica and Department of Pharmacology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Rongmin
authors.initials: R
authors.lastname: Yu
authors.affiliation: Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China. Electronic address: ding_ke@gibh.ac.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D049109:Cell Proliferation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008958:Models, Molecular; D009154:Mutation; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl; C030986:pyrimidine
keywords: Bcr-Abl(T315I); Chronic myelogenous leukemia (CML); Clinical resistance; Hybride; Pyrimidine alkynyl