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J Med Chem. 2017 Jan 12;60(1):273-289. doi: 10.1021/acs.jmedchem.6b01290. Epub 2016 Dec 14.

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.

Wang Q1,2, Liu F1,3, Wang B1,3, Zou F1,2, Qi Z1,2, Chen C1,3, Yu K1,3, Hu C1,3, Qi S1,2, Wang W1,2, Hu Z1,2, Liu J1, Wang W1,2, Wang L1,3, Liang Q1, Zhang S2,4, Ren T5, Liu Q1,2,3,5, Liu J1,2.

Author information

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.
Hefei Cosource Medicine Technology Co. Ltd. , 358 Ganquan Road, Hefei, Anhui 230031, 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.


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.

[Indexed for MEDLINE]

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