2. Academic Validation
  3. Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode

Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode

  • J Med Chem. 2017 Apr 13;60(7):2944-2962. doi: 10.1021/acs.jmedchem.6b01907.
Aoli Wang 1 2,  Xixiang Li 1 3,  Hong Wu 1 3,  Fengming Zou 1 3,  Xiao-E Yan 4,  Cheng Chen 1 2,  Chen Hu 1 2,  Kailin Yu 1 2,  Wenchao Wang 1 3,  Peng Zhao 4,  Jiaxin Wu 1 2,  Ziping Qi 1 3,  Wei Wang 1 3,  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 , Mailbox 1110, 350 Shushanhu Road, 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 , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
  • 4 Department of Biophysics and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191, 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. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
PMID: 28282122 DOI: 10.1021/acs.jmedchem.6b01907
Abstract

On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung Cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.

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