PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N-substituted piperazinone moiety were achieved. In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC₅₀ = 0.94 nM) and PARP-2 (IC₅₀ = 0.87 nM) but also toward PARP-7 (IC₅₀ = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.

中文翻译：

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发现含有哌嗪酮部分的喹唑啉-2,4(1H,3H)-二酮衍生物作为有效的 PARP-1/2 抑制剂─设计、合成、体内抗肿瘤活性和 X 射线晶体结构分析

PARP-1/2抑制剂已成为治疗HR缺陷型肿瘤的重要治疗策略。然而，发现具有改进且独特的药理学文件的新抑制剂仍需要大量探索。在此，获得了一系列带有N-取代哌嗪酮部分的新型高效PARP-1/2抑制剂。特别是，Cpd36被确定为一种独特的 PARP 抑制剂，不仅对 PARP-1 (IC ₅₀ = 0.94 nM) 和 PARP-2 (IC ₅₀ = 0.87 nM) 表现出显着的酶活性，而且对 PARP-7 (IC 50 = 0.87 nM) 也表现出_显着的酶活性。 0.21 nM)，并且比其他 PARP 同工型具有高选择性。此外，Cpd36具有口服生物利用度，并且在乳腺癌和前列腺癌异种移植模型中显着抑制肿瘤生长。PARP-1和PARP-2中Cpd36的晶体结构以及PARP-7中预测的结合模式揭示了其结合特征，并为进一步开发高效和选择性的PARP-1和/或PARP-7抑制剂提供了深刻的信息。