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发现RP-2119:一种强效,选择性和口服可生物利用的多太酶抑制剂

Philippe Mochirian¹, Robert Papp¹, Marie-Claude Mathieu¹

¹Repare Therapeutics, 7171 Frederick-Banting, Building 2, H4S 1Z9 Montréal, Québec, Canada.

Journal of medicinal chemistry

|September 8, 2025

概括

DNA聚合酶甲基 (Polθ) 是癌症治疗的目标. RP-2119,一种新的Polθ抑制剂,在与PARP抑制剂结合治疗HR缺陷癌症时显示出有前途.

科学领域:

分子生物学分子生物学
癌症治疗方法癌症治疗方法
药物发现药物发现药物发现

背景情况:

DNA聚合酶甲基 (Polθ) 对于微同质介导端结合 (MMEJ) 的DNA修复至关重要.
聚是同源重组 (HR) 缺陷的癌症的合成致命标,特别是那些具有BRCA1/BRCA2突变的癌症.
抑制Polθ在这些癌症中可能与PARP抑制剂协同作用.

研究的目的:

发现和开发RP-2119,一个有选择性和强大的Polθ ATPase抑制剂.
评估RP-2119在HR缺陷癌症模型中的临床前疗效和安全性.
评估RP-2119与olaparib在临床前癌症模型中的协同作用潜力.

主要方法:

使用冷电子显微镜 (cryo-EM) 进行高通量ATPase选和结构研究,以确定Polθ抑制剂结合部位.
优化侧重于功效和ADME属性.
在缺乏HR的癌症细胞系中进行体外细胞测试.
在体内研究使用HR缺陷细胞系和患者衍生小鼠异种移植.

主要成果:

发现RP-2119,一种选择性,强效和生物可用的Polθ ATPase抑制剂.
RP-2119在体外表现出强大的活性,对抗HR缺乏的癌症细胞系.
在HR缺乏癌症的临床前模型中,RP-2119与olaparib显著协同作用.
组合疗法没有使血液毒性恶化.

结论:

RP-2119是针对HR缺陷癌症中Polθ的有希望的候选药物.
RP-2119和olaparib的组合代表了BRCA突变癌症的潜在治疗策略.
对于进一步的临床开发,RP-2119表现出有利的临床前特征.

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