Inhibition of the low fidelity DNA polymerase Theta (Pol) is emerging as an attractive, synthetic-lethal antitumor strategy in BRCA-deficient tumors. Here we report the AI-enabled development of 3-hydroxymethyl-azetidine derivatives as a novel class of Pol inhibitors featuring central scaffolding rings. Structure-based drug design first identified as a lead compound, which was further optimized to the more potent derivative and the metabolically stable deuterated compound exhibited significant antiproliferative properties in DNA repair-compromised cells and demonstrated favorable pharmacokinetics, showcasing that 3-hydroxymethyl-azetidine is an effective bio-isostere of pyrrolidin-3-ol and emphasizing the potential of AI in medicinal chemistry for precise molecular modifications.

中文翻译：

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发现 3-羟甲基-氮杂环丁烷衍生物作为有效的聚合酶 θ 抑制剂

低保真度 DNA 聚合酶 Theta (Pol) 的抑制正在成为 BRCA 缺陷肿瘤中一种有吸引力的合成致死抗肿瘤策略。在这里，我们报告了人工智能开发的 3-羟甲基-氮杂环丁烷衍生物，作为一类具有中心支架环的新型 Pol 抑制剂。基于结构的药物设计首先确定为先导化合物，并进一步优化为更有效的衍生物，代谢稳定的氘代化合物在 DNA 修复受损的细胞中表现出显着的抗增殖特性，并表现出良好的药代动力学，表明 3-羟甲基-氮杂环丁烷是吡咯烷-3-醇的有效生物等排体，并强调人工智能在药物化学中精确分子修饰的潜力。