title: Discovery of 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-yl)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding.
abstract: The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC50: 46 nM) and c-KIT kinase (IC50: 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 μM among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors discovery.
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Zou
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Ziping
authors.initials: Z
authors.lastname: Qi
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qi
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Zhenquan
authors.initials: Z
authors.lastname: Hu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Qianmao
authors.initials: Q
authors.lastname: Liang
authors.affiliation: CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.|Hefei Cosource Medicine Technology Co. Ltd. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
authors.forename: Shanchun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.|University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.|Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.|CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
authors.forename: Jing
authors.identifier: 0000-0001-9513-3591
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D006801:Humans; D020014:K562 Cells; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000621653:4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-yl)oxy)benzamide; D001549:Benzamides; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases