2017 Fiscal Year Final Research Report
Biophysical evaluation of the interaction between tyrosine kinase and drug for elucidation of drug resistant mechanism
| Project/Area Number |
15K06978
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Structural biochemistry
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| Research Institution | Kumamoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
森岡 弘志 熊本大学, 大学院生命科学研究部(薬), 教授 (20230097)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | チロシンキナーゼ / 阻害剤 / 耐性変異体 |
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| Outline of Final Research Achievements |
Aberrant activation and over-expression of tyrosine kinases are related to various human cancer. Various tyrosine kinase inhibitors are under clinical use, while occurrence of drug resistant mutants is a severe problem. We performed biophysical analysis of the interaction between FGFR1 kinase domain and its inhibitors. It revealed that N546K mutants exhibited increased affinity for ATP, a substrate of tyrosine kinases, which assumed to cause resistance to the ATP-competitive inhibitors. The V561M mutants exhibited decreased affinity for PD173074, which was assumed to be caused not only by steric hindrance around mutation site but also by steric hindrance caused by structural change induced by mutation. These finding reveled that drug resistant mechanism of tyrosine kinase is quite complicated and detailed analysis of the interaction among the kinases, inhibitors and ATP is essential for elucidation of the drug-resistance mechanism.
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| Free Research Field |
構造生物化学
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