title: Synthesis and identification of GZD856 as an orally bioavailable Bcr-AblT315Iinhibitor overcoming acquired imatinib resistance.
abstract: Bcr-AblT315Iinduced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-AblT315Iinhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC50values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3WTand Ba/F3T315Icells with IC50values of 2.2, 0.64 and 10.8 nM. Furthermore, GZD856 potently suppressed tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I. Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance.
authors.affiliation: a School of Pharmacy , Jinan University , Guangzhou , China.|b State Key Laboratory of Respiratory Diseases , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou , China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.affiliation: a School of Pharmacy , Jinan University , Guangzhou , China.|b State Key Laboratory of Respiratory Diseases , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou , China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: b State Key Laboratory of Respiratory Diseases , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou , China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.affiliation: b State Key Laboratory of Respiratory Diseases , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou , China.
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.affiliation: a School of Pharmacy , Jinan University , Guangzhou , China.|b State Key Laboratory of Respiratory Diseases , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou , China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D020014:K562 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D015394:Molecular Structure
chemical_list: D001549:Benzamides; C000609603:GZD856; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: Bcr-Abl; T315I mutant; chronic myelogenous leukemia; imatinib clinical resistance; scaffold hopping