Development of a new macrolide derivative targeting mTORC

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07182
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Iwate Medical University
• Principal Investigator: Nishiya Naoyuki 岩手医科大学, 薬学部, 教授 (10286867)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Wnt / 阻害薬 / mTOR / 悪性腫瘍

Outline of Final Research Achievements

In cancer molecular targeted therapy, the progress of kinase inhibitors has been remarkable, but the identificationｓ of breakthrough drugs and new therapeutic targets remain as important issues. Recently, we have found that the Wnt signal inhibition by ivermectin (IVM) is mediated by binding to TELO2, one of the components of the mTOR complex. This is an attractive cancer treatment strategy with a new mechanism, but overdosing of IVM causes central nervous system depression through binding to inhibitory neurotransmitter receptors. In this study, we hypothesized that "both of enhancing the Wnt signal inhibitory activity and reducing central nervous system depression can be achieved by derivatizing IVM" and synthesized a lead compound for a Wnt signal inhibitor that acts through TELO2.

Free Research Field

創薬科学

Academic Significance and Societal Importance of the Research Achievements

がん分子標的治療ではキナーゼ阻害剤の躍進が著しいが、それに続く画期的な薬剤や新たな治療標的の同定が重要な課題である。様々ながんの病態に関与するWnt経路は抗がん剤の標的として魅力的であるが、同経路は多様な生理機能を有するため、その主要な構成因子を標的にした際にはオンターゲットの副作用を回避することは困難である。我々の研究は、一部の悪性腫瘍がその生存に必要とするWnt経路制御因子TELO2を標的とした創薬の基盤を形成する。さらに、TELO2阻害活性を有するイベルメクチンの構造改変を進めることで、長期にわたる繰り返し投与を可能とする低毒性のリード化合物を創成した。