Discovery of novel therapeutic agents for biliary tract and pancreatic cancer based on antifungal agents

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03533
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Keio University
• Principal Investigator: Yoshimasa Saito 慶應義塾大学, 薬学部(芝共立), 教授 (90360114)
• Co-Investigator(Kenkyū-buntansha): 大江 知之 慶應義塾大学, 薬学部(芝共立), 准教授 (30624283)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 胆道がん / 膵臓がん / オルガノイド / 抗真菌薬

Outline of Final Research Achievements

We have elucidated the molecular mechanisms of antitumor effects of antifungal agents identified as hit compounds in the screening of existing drugs using biliary tract and pancreatic cancer organoids, and verified their antitumor effects in vivo using experimental animals.
Furthermore, we designed and synthesized more than 50 new derivatives based on the structures of azole antifungals such as fenticonazole. Evaluation of physical properties and ADME properties as well as activity using organoids led to the discovery of promising compounds with growth inhibitory activity comparable to that of fenticonazole, with improved metabolic stability, water solubility, and CYP inhibition. Furthermore, we succeeded in synthesizing prodrugs of these compounds by introducing carboxy groups.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果から、抗真菌薬がβ-catenin経路を抑制することにより、胆道・膵臓がん細胞の増殖を抑制することが明らかになった。また、胆道がんを移植したマウスを用いた検討において、経口抗真菌薬であるイトラコナゾールがin vivoで抗腫瘍効果を示した。さらに、既存の抗真菌薬をリード化合物として構造展開を行うことにより、胆道・膵臓がんに対する新たな低分子化合物を創出した。今後はPOCの取得、医師主導治験などを目指している。これらの新規化合物が手術適応のない胆道・膵臓がんの患者に対して最小限の副作用で腫瘍全体を退縮させ、生存期間を延長させる革新的な治療薬となることが期待される。