Development of anticancer drug based on AP site repair inhibition

• Project/Area Number: 17K15482
• 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: Abe Yukiko 九州大学, 薬学研究院, 助教 (40586856)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: APサイト修復阻害 / 共有結合形成 / 医薬分子設計 / DNA脱塩基部位

Outline of Final Research Achievements

In this study, we investigate the new AP site-binding ligands having thioguanine unit and polyamine unit. the thioguanine ligands formed the hidrogen bonding with complementary cytosine base and stabilized the duplexes having AP sites analogue. In the experiments of thioguanine ligand using the duplexes having AP sites, it was indicated that the thioguanine ligands promoted the cleavage of AP sites by b-elimination followed by formed the covalent bond with the b-eliminated product of AP sites. We expect that the adducts of thioguanine ligand with the b-eliminated product to work as the 3'-block and that the blockage or modulation of the AP site repair pathway may enhance the antitumor efficacy of DNA alkylating agents in combination with the thioguanine ligands.

Academic Significance and Societal Importance of the Research Achievements

本研究を通して開発したチオグアニンリガンドは、代表的なDNA損傷の一つであるAPサイトを特異的に認識し、APサイト部位での切断を促進する。更には、APサイトの切断産物と共有結合を形成する事で、APサイト修復を阻害すると期待される。本リガンドはAPサイト修復阻害に基づく新規抗がん剤および既存抗がん剤との併用による抗がん効果増強剤として有用なツールとなりうる。