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

  • J Med Chem. 2017 Jan 12;60(1):273-289. doi: 10.1021/acs.jmedchem.6b01290.
Qiang Wang  1  2 ,  Feiyang Liu  1  3 ,  Beilei Wang  1  3 ,  Fengming Zou  1  2 ,  Ziping Qi  1  2 ,  Cheng Chen  1  3 ,  Kailin Yu  1  3 ,  Chen Hu  1  3 ,  Shuang Qi  1  2 ,  Wenchao Wang  1  2 ,  Zhenquan Hu  1  2 ,  Juan Liu  1 ,  Wei Wang  1  2 ,  Li Wang  1  3 ,  Qianmao Liang  1 ,  Shanchun Zhang  2  4 ,  Tao Ren  5 ,  Qingsong Liu  1  2  3  5 ,  Jing Liu  1  2
Affiliations
  • 1. High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
  • 2. CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei Anhui 230031, P. R. China.
  • 3. University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
  • 4. Hefei Cosource Medicine Technology Co. Ltd. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
  • 5. Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.
PMID: 27966954 DOI: 10.1021/acs.jmedchem.6b01290
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.

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