title: Design, synthesis, and biological activity of 4-(imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-phenylbenzamide derivatives as BCR-ABL kinase inhibitors.
abstract: A series of 4-((pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-((imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-)phenyl-3-benzamide derivatives were designed, synthesized as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. These new compounds were screened for BCR-ABL1 kinase inhibitory activity, and most of them appeared good inhibitory activity against BCR-ABL1 kinase. One of the most potent compounds 16a strongly suppressed BCR-ABL1 kinase with IC50value of 8.5nM. The tested compounds 16a and 16i showed strong inhibitory activities against K562 with IC50value of less than 2nM. Molecular docking studies indicated that these compounds fitted well with the active site of BCR-ABL1 protein. The results showed these inhibitors may serve as lead compounds for further developing new drugs targeted BCR-ABL kinase.
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China. Electronic address: huliming@bjut.edu.cn.
authors.forename: Liming
authors.initials: L
authors.lastname: Hu
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Cao
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
authors.forename: Yongjuan
authors.initials: Y
authors.lastname: Lv
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Beijing Scitech-MQ Pharmaceuticals Limited, Beijing 101320, China.
authors.forename: Leifu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Beijing Scitech-MQ Pharmaceuticals Limited, Beijing 101320, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
mesh_terms: D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D016044:Fusion Proteins, bcr-abl
keywords: BCR–ABL inhibitors; Bioactivity; Chronic myeloid leukemia; Molecular docking