Development of highly target selective covalent inhibitors

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15483
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kyushu University
• Principal Investigator: Shindo Naoya 九州大学, 薬学研究院, 助教 (20722490)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: タンパク質 / コバレントドラッグ / EGFR / CFA / システイン / 有機化学

Outline of Final Research Achievements

Irreversible inhibition of protein function by forming a covalent bond can provide therapeutic benefits compared to reversible inhibition, including enhanced and sustained pharmacological potency and protein isoform selectivity. In this research, we employed α-chlorofluoroacetamide (CFA) group as a weakly reactive, cysteine-directed warhead in the design of highly target selective covalent inhibitors. Based on the molecular architecture of osimertinib, an FDA-approved irreversible EGFR inhibitor, various CFA-appended derivatives were synthesized. From SAR studies using cell antiproliferative assay, we identified a CFA-based novel covalent inhibitor which exhibits potent inhibitory activity against gefitinib-resistant H1975 cell lines. In vivo efficacy of the compound was also evaluated using a mouse xenograft model.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

コバレント阻害剤は共有結合によって標的タンパク質の機能を不可逆的に阻害する薬剤で、可逆的な薬と比べ強く持続的な薬効など優れた特長を示す。一方、標的以外のタンパク質の非特異ラベル化は毒性の原因となるため、標的選択性が極めて重要である。本研究では、申請者らが見出した、システイン残基と穏やかに反応するクロロフルオロアセタミド（CFA）基を利用し、非小細胞肺癌の分子標的であるEGFRの高選択的不可逆阻害剤の開発を検討した。既承認の第三世代EGFR阻害剤であるオシメルチニブを鋳型に、反応基としてCFA基を有する誘導体を合成・評価した結果、オシメルチニブと同等の活性と、優れた選択性を示す化合物を見出した。