Research Papers:

Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation

Aoli Wang, Xiao-E Yan, Hong Wu, Wenchao Wang, Chen Hu, Cheng Chen, Zheng Zhao, Peng Zhao, Xixiang Li, Li Wang, Beilei Wang, Zi Ye, Jinhua Wang, Chu Wang, Wei Zhang, Nathanael S. Gray, Ellen L. Weisberg, Liang Chen, Jing Liu, Cai-Hong Yun and Qingsong Liu _

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Oncotarget. 2016; 7:69760-69769. https://doi.org/10.18632/oncotarget.11951

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Aoli Wang1,2,*, Xiao-E Yan3,*, Hong Wu1,2,*, Wenchao Wang1,4,*, Chen Hu1,2, Cheng Chen1,2, Zheng Zhao1,4, Peng Zhao3, Xixiang Li1, Li Wang1,2, Beilei Wang1,2, Zi Ye5, Jinhua Wang6,9, Chu Wang5, Wei Zhang7, Nathanael S. Gray6,9, Ellen L. Weisberg8, Liang Chen7, Jing Liu1,4, Cai-Hong Yun3, Qingsong Liu1,2,4

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

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

3Institute 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

4Hefei Science Center, Chinese Academy of Sciences, Anhui, Hefei 230031, P. R. China

5Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, P. R. China

6Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

7Collaborative Innovation Center of Cancer Medicine, National Institute of Biological Sciences, Beijing 102206, P. R. China

8Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

9Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA

*These authors contributed equally to this work

Correspondence to:

Jing Liu, email: jingliu@hmfl.ac.cn

Cai-Hong Yun, email: yunch@hsc.pku.edu.cn

Qingsong Liu, email: qsliu97@hmfl.ac.cn

Keywords: Ibrutinib, EGFR kinase, DFG-in/c-Helix-out, inactive conformation, NSCLC

Received: June 08, 2016     Accepted: September 05, 2016     Published: September 10, 2016


Ibrutinib, a clinically approved irreversible BTK kinase inhibitor for Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) etc, has been reported to be potent against EGFR mutant kinase and currently being evaluated in clinic for Non Small Cell Lung Cancer (NSCLC). Through EGFR wt/mutant engineered isogenic BaF3 cell lines we confirmed the irreversible binding mode of Ibrutinib with EGFR wt/mutant kinase via Cys797. However, comparing to typical irreversible EGFR inhibitor, such as WZ4002, the washing-out experiments revealed a much less efficient covalent binding for Ibrutinib. The biochemical binding affinity examination in the EGFR L858R/T790M kinase revealed that, comparing to more efficient irreversible inhibitor WZ4002 (Kd: 0.074 μM), Ibrutinib exhibited less efficient binding (Kd: 0.18 μM). An X-ray crystal structure of EGFR (T790M) in complex with Ibrutinib exhibited a unique DFG-in/c-Helix-out inactive binding conformation, which partially explained the less efficiency of covalent binding and provided insight for further development of highly efficient irreversible binding inhibitor for the EGFR mutant kinase. These results also imply that, unlike the canonical irreversible inhibitor, sustained effective concentration might be required for Ibrutinib in order to achieve the maximal efficacy in the clinic application against EGFR driven NSCLC.

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