title: Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib.
abstract: Bcr-Abl(T315I) mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.
authors.affiliation: Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Pan
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Li
authors.forename: Donghai
authors.initials: D
authors.lastname: Wen
authors.forename: Huoyou
authors.initials: H
authors.lastname: Long
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.forename: Yubing
authors.initials: Y
authors.lastname: Feng
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhuang
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Zhang
authors.forename: Jianqi
authors.initials: J
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Leng
authors.forename: Xingfen
authors.initials: X
authors.lastname: Lang
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.forename: Miaoqin
authors.initials: M
authors.lastname: She
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D000480:Alkynes; D010880:Piperidines; D011725:Pyridines
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; C579813:olverembatinib; D000480:Alkynes; D010880:Piperidines; D011725:Pyridines