Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

中文翻译：

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5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide的发现（ AZD5305)：一种 PARP1–DNA 捕集器，对 PARP1 的选择性高于 PARP2 和其他 PARP

聚 ADP 核糖聚合酶 (PARP) 抑制剂已在肿瘤学中获得监管批准，用于治疗包括 BRCA 突变在内的同源重组修复缺陷肿瘤。然而，有些与一线化疗联合失败，通常是由于重叠的血液学毒性。目前批准的 PARP 抑制剂缺乏对 PARP1 的选择性，而不是 PARP2 和其他 16 个 PARP 家族成员，我们假设这可能导致毒性。最近的文献表明，PARP1 抑制和 PARP1-DNA 捕获是在 BRCA 突变背景中提高功效的关键。在这里，我们描述了25 (AZD5305)的基于结构和性能的设计，这是一种有效且选择性的 PARP1 抑制剂和 PARP1-DNA 捕集器，在 BRCA 突变体 HBCx-17 PDX 模型中具有出色的体内功效。化合物25对PARP1的选择性高于其他PARP家族成员，具有良好的次要药理学和理化性质，在临床前物种中具有优异的药代动力学，体外对人骨髓祖细胞的影响降低。