Development of innovative cancer therapy using novel CDK inhibitors that exhibit highly cell-specific anticancer effects

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07626
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: OHASHI Yoshimi 公益財団法人がん研究会, がん化学療法センター 分子薬理部, 主任研究助手 (50727427)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: サイクリン依存性キナーぜ / RNAポリメラーゼII / 転写調節 / 細胞死 / 分子標的薬

Outline of Final Research Achievements

In this study, we identified a novel synthetic derivative of the marine natural product Lamellarin N, Azalam 4, that broadly inhibited cyclin dependent kinases (CDKs) at the nanomolar level. We demonstrated that this compound showed a strong anticancer efficacy via apoptosis only on 4 of the 39 cancer cells examined, exhibiting similar anticancer selectivity and gene expression changes to several previously developed transcriptional CDK inhibitors. Furthermore, it was also effective in animal models against cancer cell lines that induced cell death in cellular level. Since Azalam 4 showed the highest anticancer specificity among the transcriptional CDK inhibitors examined, this compound would be a promising lead compound for the novel antitumor drug candidates that target transcriptional CDKs.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、Azalam4や先行して開発された転写調節型CDK阻害剤が、高い細胞特異性でアポトーシスを誘導する抗がん剤候補であることが示された。現在、Azalam4を含む転写調節型CDK阻害剤の薬効予測を実現するために、アポトーシス誘導を起こす細胞特異性を規定する分子の探索を進めている。これにより、転写調節型CDK阻害剤の開発が加速化するとともに、転写調節型CDK阻害剤の治療効果が高い患者の層別化に役立つものと考えられる。