2. Academic Validation
  3. 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

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

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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