| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Shen, Xiaokun Chen, Beibei Ma, Zhaosheng Xie, Bojian Cao, Xinguang Yang, Tiejun Zhao, Yuzhou Qin, Jianjun Li, Jicheng Cao, Feilin Chen, Xiaobing |
| Description |
Author Affiliation: Shen X ( a Institute of Cell Biology, Zhejiang University , Hangzhou , P.R. China .); Chen B ( b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.); Ma Z ( c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.); Xie B ( b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.); Cao X ( b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.); Yang T ( c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.); Zhao Y ( c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.); Qin J ( c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.); Li J ( c Department of Internal Oncology , Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China.); Cao F ( a Institute of Cell Biology, Zhejiang University , Hangzhou , P.R. China .); Chen X ( b Department of Surgical Oncology , Taizhou Hospital, Wenzhou Medical University , Taizhou , P.R. China , and.) |
| Abstract |
Human epidermal growth factor receptor 2 (HER2) has become a well-established target for the treatment of HER2-positive lung cancer. However, a frequently observed in-frame mutation that inserts amino acid quadruplex Tyr776-Val777-Met778-Ala779 at G776 (G776(YVMA)) in HER2 kinase domain can cause drug resistance and sensitivity, largely limiting the application of reversible tyrosine kinase inhibitors in lung cancer therapy. A systematic investigation of the intermolecular interactions between the HER2(YVMA) mutant and clinical small-molecule inhibitors would help to establish a complete picture of drug response to HER2 G776(YVMA) insertion in lung cancer, and to design new tyrosine kinase inhibitors with high potency and selectivity to target the lung cancer-related HER2(YVMA) mutant. Here, we combined homology modeling, ligand grafting, structure minimization, molecular simulation and binding affinity analysis to profile a number of tyrosine kinase inhibitors against the G776(YVMA) insertion in HER2. It is found that the insertion is far away from HER2 active pocket and thus cannot contact inhibitor ligand directly. However, the insertion is expected to induce marked allosteric effect on some regions around the pocket, including A-loop and hinges connecting between the N- and C-lobes of HER2 kinase domain, which may exert indirect influence to inhibitor binding. Most investigated inhibitors exhibit weak binding strength to both wild-type and mutant HER2, which can be attributed to steric hindrance that impairs ligand compatibility with HER2 active pocket. However, the cognate inhibitor lapatinib and the non-cognate inhibitor bosutinib were predicted to have low affinity for wild-type HER2 but high affinity for HER2(YVMA) mutant, which was confirmed by subsequent kinase assay experiments; the inhibitory potencies of bosutinib against wild-type and mutant HER2 were determined to be IC(50) > 1000 and =27 nM, respectively, suggesting that the bosutinib might be exploited as a selective inhibitor for mutant over wild-type HER2. Structural examination revealed that formation of additional non-bonded interactions such as hydrogen bonds and hydrophobic contacts with HER2 A-loop region due to G776(YVMA) insertion is the primary factor to improve bosutinib affinity upon the mutation. |
| File Format |
HTM / HTML |
| ISSN |
10799893 |
| Issue Number |
1 |
| Volume Number |
36 |
| e-ISSN |
15324281 |
| Journal |
Journal of Receptors and Signal Transduction |
| Language |
English |
| Publisher |
Taylor & Francis |
| Publisher Date |
2016-01-01 |
| Publisher Place |
Great Britain (UK) |
| Access Restriction |
One Nation One Subscription (ONOS) |
| Subject Keyword |
Discipline Cell Biology Discipline Physiology Discipline Biochemistry Drug Resistance, Neoplasm Genetics Lung Neoplasms Drug Therapy Mutation Protein Kinase Inhibitors Pharmacology Receptor, Erbb-2 Small Molecule Libraries Humans Models, Molecular Molecular Dynamics Simulation Mutagenesis, Insertional Protein Binding Protein Conformation Chemistry Journal Article Research Support, Non-u.s. Gov't |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
