PO.ET09.07 · 实验与分子治疗

针对HR功能正常肿瘤的高效RAD51抑制剂，具备同类首创潜力

Highly potent inhibitors of RAD51, with first-in-class potential, targeting HR-proficient cancers

编号 4574 展板 17 时间 4/21 09:00–12:00 区域 Section 17 主讲 Alessia Montagnoli, PhD

分会场 Novel Antitumor Agents 2

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作者与单位 Authors & Affiliations

Alessandro Galbiati, Daniela Asa, Pietro Picconi, Annamaria Marra, Claudia Stellato, Patrizia Banfi, Liviana Cozzi, Fabio Gasparri, Frank Narjes, Claudia Perrera, Alessia Montagnoli

Nerviano Medical Sciences, Nerviano, Italy

摘要 Abstract

中文摘要

背景：通过靶向DNA修复通路选择性清除癌细胞已取得巨大成功，多个PARP1抑制剂（PARPi）已在不同实体瘤适应证中获批。RAD51是一个关键的DNA修复基因，通过介导同源重组修复（HRR）和促进复制叉保护，在维持基因组稳定性中发挥重要作用。HRR受损会降低具有高复制应激遗传背景的细胞适应度，并使癌细胞对DNA损伤剂和DNA损伤应答（DDR）抑制剂敏感。方法：开展了一项药物发现项目，以鉴定BRCA2-RAD51蛋白-蛋白相互作用（PPI）的新型小分子抑制剂。采用基于结构的药物设计开发了多个化合物系列。使用荧光偏振（FP）测定法和ATPase测定法评估生化效力，后者用于测量依赖于RAD51自身寡聚化的RAD51 DNA诱导活性。开发了用于测量HRR功能的细胞报告基因测定法和用于测量RAD51病灶形成的高内涵成像测定法，以评估化合物的靶点结合。结果：我们已鉴定出具有专利权的RAD51 PPI抑制剂，其具有口服生物利用度，对RAD51表现出个位数纳摩尔级生化效力，并在一部分癌细胞系中表现出抗增殖活性。这些细胞系包括对顺铂或PARP1抑制剂耐药的细胞系，其敏感性特征不同于RAD51基因缺失（基于DepMap数据集的分析）。抗增殖效力与生化效力、细胞靶点结合以及DNA损伤应答的激活相关，证实了预期的靶向作用机制。结论：这种新颖的作用机制，以及与DNA损伤剂和DDR抑制剂联用的潜力，使Nerviano Medical Sciences的RAD51抑制剂成为有前景的同类首创候选药物，可在多种对标准治疗耐药的癌症类型中进一步开发。

查看英文原文 English abstract

BACKGROUND: Targeting DNA repair pathways to selectively eliminate cancer cells has seen a huge success with multiple PARP1 inhibitors (PARPi) approved in different solid tumor indications. RAD51 is a key DNA repair gene with an important role in maintaining genomic stability by mediating homologous recombination repair (HRR) and promoting replication fork protection. Impairment of HRR reduces cell fitness in genetic backgrounds with high replication stress and sensitizes cancer cells to DNA-damaging agents and DNA Damage Response (DDR) inhibitors. METHODS: A drug discovery campaign was conducted to identify novel small-molecule inhibitors of BRCA2-RAD51 protein-protein interaction (PPI). Structure-based drug design was employed to develop multiple compound series. Biochemical potency was assessed using a Fluorescence Polarization (FP) assay and an ATPase assay to measure the DNA-induced activity of RAD51, which is reliant on RAD51 self-oligomerization. A cellular reporter assay to measure HRR proficiency and a high content imaging assay to measure RAD51 foci formation were developed to assess compounds target engagement. RESULTS: We have identified proprietary RAD51 PPI inhibitors, orally bioavailable, demonstrating single-digit nanomolar biochemical potency on RAD51 and anti-proliferative activity in a subset of cancer cell lines. These include cell lines resistant to cisplatin or PARP1 inhibitors with a sensitivity profile distinct from RAD51 genetic depletion (based on the analysis of DepMap dataset). The anti-proliferative potency correlates with biochemical potency, cellular target engagement and activation of DNA damage response, confirming the expected on-target mechanism of action. CONCLUSIONS: The novel mechanism of action, with potential for combination with DNA damaging agents and DDR inhibitors, positions Nerviano Medical Sciences' RAD51 inhibitors as promising first-in-class candidates for further development across multiple cancer types resistant to standard of care.

利益披露 Disclosure

A. Galbiati, None.. D. Asa, None.. P. Picconi, None.. A. Marra, None.. C. Stellato, None.. P. Banfi, None.. L. Cozzi, None.. F. Gasparri, None.. F. Narjes, None.. A. Montagnoli, None.

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