2. Academic Validation
  3. Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode

Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode

  • Oncotarget. 2017 Mar 14;8(11):18359-18372. doi: 10.18632/oncotarget.15443.
Chen Hu 1 2,  Aoli Wang 1 2,  Hong Wu 1 3,  Ziping Qi 1 3,  Xixiang Li 1 3,  Xiao-E Yan 4,  Cheng Chen 1 2,  Kailin Yu 1 2,  Fengming Zou 1 3,  Wenchao Wang 1 3,  Wei Wang 1 3,  Jiaxin Wu 1 2,  Juan Liu 1 2,  Beilei Wang 1 2,  Li Wang 1 2,  Tao Ren 5,  Shanchun Zhang 3 6,  Cai-Hong Yun 4,  Jing Liu 1 3,  Qingsong Liu 1 2 3 5
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 2 University of Science and Technology of China, Hefei, Anhui 230036, P. R. China.
  • 3 CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui 230031, P. R. China.
  • 4 Institute of Systems Biomedicine, Department of Biophysics, Beijing Key Laboratory of Tumor Systems Biology and Center for Molecular and Translational Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, 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.
  • 6 Hefei Cosource Medicine Technology Co. LTD., Hefei, Anhui 230031, P. R. China.
PMID: 28407693 DOI: 10.18632/oncotarget.15443
Abstract

EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible Btk kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct "DFG-in" and "cHelix-out" inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of Apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose.

Keywords

EGFR; EGFRT790M; NSCLC; drug resistance; kinase inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15772
    99.96%, Mutant-Selective EGFR Inhibitor