title: Expanding the structural diversity of Bcr-Abl inhibitors: Dibenzoylpiperazin incorporated with 1H-indazol-3-amine.
abstract: A series of N,N'-dibenzoylpiperazine derivatives incorporated with 1H-indazol-3-amine have been designed, synthesized and evaluated as novel Bcr-Abl inhibitors. Several title compounds exhibited potent inhibitory activity against Bcr-Abl wild type as well as T315I mutant. Two compounds, 11a and 12c, strongly suppressed the activity of native and mutant Bcr-Abl. In particular, 11a exhibited comparable potency with that of Imatinib. It potently inhibited both Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 values of 0.014 μM and 0.45 μM, respectively. Furthermore, compound 11a also inhibited the proliferation of K562 leukemia cancer cells. Therefore, it could serve as promising lead compound for further optimization of Bcr-Abl(WT) and Bcr-Abl(T315I) inhibitors.
authors.affiliation: Department of Pharmacy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shan
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Dong
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Pharmacy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China. Electronic address: wangmy28@126.com.
authors.forename: Maoyi
authors.initials: M
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000609860:1H-indazol-3-amine; D000970:Antineoplastic Agents; D007191:Indazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C000609859:N,N'-dibenzoylpiperazine; D016044:Fusion Proteins, bcr-abl
keywords: ATP-Binding site; Bcr-Abl; Flexible linker; Hinge-binding fragment; Resistance