Poly(ADP-ribose) polymerase (PARP) enzymes play an important role in repairing DNA damage and maintaining genomic stability. Olaparib, the first-in-class PARP inhibitor, has shown remarkable clinical benefits in the treatment of BRCA-mutated ovarian or breast cancer. However, the undesirable hematological toxicity and pharmacokinetic properties of olaparib limit its clinical application. Here, we report the first preclinical characterization of fluzoparib (code name: SHR-3162), a novel, potent, and orally available inhibitor of PARP. Fluzoparib potently inhibited PARP1 enzyme activity and induced DNA double-strand breaks, G2 /M arrest, and apoptosis in homologous recombination repair (HR)-deficient cells. Fluzoparib preferentially inhibited the proliferation of HR-deficient cells and sensitized both HR-deficient and HR-proficient cells to cytotoxic drugs. Notably, fluzoparib showed good pharmacokinetic properties, favorable toxicity profile, and superior antitumor activity in HR-deficient xenografts models. Furthermore, fluzoparib in combination with apatinib or with apatinib plus paclitaxel elicited significantly improved antitumor responses without extra toxicity. Based on these findings, studies to evaluate the efficacy and safety of fluzoparib (phase II) and those two combinations (phase I) have been initiated. Taken together, our results implicate fluzoparib as a novel attractive PARP inhibitor.

中文翻译：

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氟佐帕尼是一种新型的聚（ADP-核糖）聚合酶抑制剂，目前正在进行临床试验，具有药理学特性。

聚（ADP-核糖）聚合酶（PARP）酶在修复DNA损伤和维持基因组稳定性方面起着重要作用。一流的PARP抑制剂Olaparib在治疗BRCA突变的卵巢癌或乳腺癌中已显示出显着的临床益处。但是，奥拉帕尼的不良血液学毒性和药代动力学特性限制了其临床应用。在这里，我们报告氟佐帕利的首次临床前表征（代号：SHR-3162），一种新颖，有效且可口服的PARP抑制剂。Fluzoparib在同源重组修复（HR）缺陷型细胞中有效抑制PARP1酶活性并诱导DNA双链断裂，G2 / M阻滞和凋亡。Fluzoparib优先抑制HR缺乏细胞的增殖，并使HR缺乏和HR熟练的细胞对细胞毒性药物敏感。值得注意的是，在缺乏HR的异种移植模型中，氟佐帕利显示出良好的药代动力学特性，良好的毒性谱和优异的抗肿瘤活性。此外，氟佐帕利与阿帕替尼或与阿帕替尼加紫杉醇的组合引起明显改善的抗肿瘤反应，而没有额外的毒性。基于这些发现，已经开始进行研究以评估氟佐帕尼（II期）和这两种组合（I期）的疗效和安全性。综上所述，我们的结果暗示氟佐帕尼是一种新颖的，有吸引力的PARP抑制剂。HR缺乏异种移植模型中具有良好的抗肿瘤活性。此外，氟佐帕利与阿帕替尼或与阿帕替尼加紫杉醇的组合引起明显改善的抗肿瘤反应，而没有额外的毒性。基于这些发现，已经开始进行研究以评估氟佐帕尼（II期）和这两种组合（I期）的疗效和安全性。综上所述，我们的结果暗示氟佐帕尼是一种新颖的，有吸引力的PARP抑制剂。HR缺乏异种移植模型中具有良好的抗肿瘤活性。此外，氟佐帕利与阿帕替尼或与阿帕替尼加紫杉醇的组合引起明显改善的抗肿瘤反应，而没有额外的毒性。基于这些发现，已经开始进行研究以评估氟佐帕尼（II期）和这两种组合（I期）的疗效和安全性。综上所述，我们的结果暗示氟佐帕尼是一种新颖的，有吸引力的PARP抑制剂。