Elucidation of inhibition mechanism of kinesin motor to develop anti-cancer drugs

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07316
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Tokyo University of Science
• Principal Investigator: Yokoyama Hideshi 東京理科大学, 薬学部生命創薬科学科, 准教授 (70433208)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: X線結晶構造解析 / 等温滴定型カロリメトリー / キネシンモーター / 阻害剤

Outline of Final Research Achievements

In this study, I tried to determine the structures of the mitotic kinesin Eg5 and CENP-E and the complexes with their inhibitors were determined to elucidate the binding and inhibition mechanisms of the inhibitors and to develop novel anti-cancer drugs. For Eg5 motor domain, I performed X-ray crystal structure determination and isothermal titration calorimetry analyses, and elucidated the inhibition mechanisms. For CENP-E motor domain, I determined the crystal structure in higher resolution than the previous report, and elucidate the structural feature.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

細胞分裂期特異的なキネシンモータータンパク質CENP-EやEg5とそれらの阻害剤との複合体構造解析による、阻害剤の結合阻害の機構を解明することで、新規な抗がん剤を設計する構造基盤が得られた。既存のタキサン、ビンカアルカロイドなどの微小管阻害剤と異なり、キネシンモーターの阻害剤は非分裂期の微小管には作用しないため、副作用の少ない抗がん剤のリード化合物として期待できる。