Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy,Journal of Medicinal Chemistry

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Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-05-03 , DOI: 10.1021/acs.jmedchem.2c02101
Maria Chiara Pismataro ₁ , Andrea Astolfi ₁ , Maria Letizia Barreca ₁ , Martina Pacetti ₁ , Silvia Schenone ₂ , Tiziano Bandiera ₃ , Anna Carbone ₂ , Serena Massari ₁

Affiliation

Synthetic lethality (SL) is an innovative strategy in targeted anticancer therapy that exploits tumor genetic vulnerabilities. This topic has come to the forefront in recent years, as witnessed by the increased number of publications since 2007. The first proof of concept for the effectiveness of SL was provided by the approval of poly(ADP-ribose)polymerase inhibitors, which exploit a SL interaction in BRCA-deficient cells, although their use is limited by resistance. Searching for additional SL interactions involving BRCA mutations, the DNA polymerase theta (POLθ) emerged as an exciting target. This review summarizes, for the first time, the POLθ polymerase and helicase inhibitors reported to date. Compounds are described focusing on chemical structure and biological activity. With the aim to enable further drug discovery efforts in interrogating POLθ as a target, we propose a plausible pharmacophore model for POLθ-pol inhibitors and provide a structural analysis of the known POLθ ligand binding sites.

中文翻译：

靶向 DNA 聚合酶 Theta (POLθ) 的小分子作为有望用于精准癌症治疗的合成致死剂

合成致死（SL）是一种利用肿瘤遗传弱点的靶向抗癌治疗的创新策略。近年来，这一主题已成为热门话题，自 2007 年以来出版物数量的增加就证明了这一点。聚（ADP-核糖）聚合酶抑制剂的批准提供了 SL 有效性的第一个概念证明，该抑制剂利用了SL 在 BRCA 缺陷细胞中相互作用，尽管它们的使用受到耐药性的限制。在寻找涉及 BRCA 突变的其他 SL 相互作用时，DNA 聚合酶 theta (POLθ) 成为一个令人兴奋的目标。本综述首次总结了迄今为止报道的 POLθ 聚合酶和解旋酶抑制剂。化合物的描述侧重于化学结构和生物活性。为了进一步以 POLθ 作为靶标进行药物发现工作，我们提出了 POLθ-pol 抑制剂的合理药效团模型，并提供了已知 POLθ 配体结合位点的结构分析。

更新日期：2023-05-03

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