Research Papers:

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

Chen Hu, Aoli Wang, Hong Wu, Ziping Qi, Xixiang Li, Xiao-E Yan, Cheng Chen, Kailin Yu, Fengming Zou, Wenchao Wang, Wei Wang, Jiaxin Wu, Juan Liu, Beilei Wang, Li Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun _, Jing Liu and Qingsong Liu

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Oncotarget. 2017; 8:18359-18372. https://doi.org/10.18632/oncotarget.15443

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Chen Hu1,2,*, Aoli Wang1,2,*, Hong Wu1,3,*, Ziping Qi1,3,*, Xixiang Li1,3,*, Xiao-E Yan4,*, Cheng Chen1,2, Kailin Yu1,2, Fengming Zou1,3, Wenchao Wang1,3, Wei Wang1,3, Jiaxin Wu1,2, Juan Liu1,2, Beilei Wang1,2, Li Wang1,2, Tao Ren5, Shanchun Zhang3,6, Cai-Hong Yun4, Jing Liu1,3, Qingsong Liu1,2,3,5

1High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China

2University of Science and Technology of China, Hefei, Anhui 230036, P. R. China

3CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, Anhui 230031, P. R. China

4Institute 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

5Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, P. R. China

6Hefei Cosource Medicine Technology Co. LTD., Hefei, Anhui 230031, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Cai-Hong Yun, email: [email protected]

Jing Liu, email: [email protected]

Qingsong Liu, email: [email protected]

Keywords: EGFR, EGFRT790M, NSCLC, kinase inhibitors, drug resistance

Received: December 09, 2016     Accepted: January 23, 2017     Published: February 17, 2017


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.

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