Development of novel antibody-drug conjugates utilizing the KSP inhibition of cysteine derivatives

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06969
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: University of Shizuoka
• Principal Investigator: Ogo Naohisa 静岡県立大学, 薬学研究院, 講師 (20501307)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 抗体薬物複合体 / 抗がん / in silico / 構造活性相関 / システイン誘導体 / KSP / Trastuzumab / プロドラッグ

Outline of Final Research Achievements

We previously synthesized S-trityl-L-cysteine (STLC) derivatives as potent KSP inhibitors. Clinical trials of KSP inhibitors have been limited by their toxicity to non-cancer cells. The approved antibody-drug conjugates (ADCs) are mainly comprised of payload classes mostly limited to tubulin binders or DNA interacting agents. The development of new payloads with new mode of action is highly desired. In this study, we designed and synthesized linker-STLC derivatives. LP-1b has a PEG linker, and LP-2b has a cleavable linker that can be cleaved by cathepsin B. In addition, we synthesized a new derivative in which S atom was substituted with C. The novel ADC-1 of LP1b and trastuzumab was confirmed to significantly inhibit cell proliferation of HER2-positive SKOV-3 cells compared to trastuzumab. For LP-2b, it was confirmed by LC-MS that the addition of cathepsin B cleaves the linker and releases the drug. These results indicated that STLC derivatives can be applied for novel ADCs.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

KSP阻害システイン誘導体を有するリンカーペイロードライブラリー構築と抗体との複合化、ADCとしての生物活性評価により、現在開発中のADCを含め抗体に結合させる低分子化合物（ペイロード）に新規作用機序を持つペイロード開発の可能性拡大が示された。また本研究成果から、KSP阻害剤を臨床応用するための学術的な裏付けとなる基礎研究の前進に貢献することができた。