Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination
Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination
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DOI：
10.1021/jm5018237
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发表时间：
2015-04-23
影响因子：
7.3
通讯作者：
Toniatti, Carlo
中科院分区：
文献类型：
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作者：
Jones, Philip;Wilcoxen, Keith;Toniatti, Carlo
聚（ADP-核糖）聚合酶（Poly（ADP-ribose）polymerases，PARP）参与内源性或外源性损伤后的DNA修复。在过去的十年中已经清楚的是，在其他DNA修复机制缺陷的背景下抑制PARP提供了一种杀死癌细胞的肿瘤特异性方式。我们描述了这种方法的原理以及Niraparib的设计和发现，Niraparib是一种强效PARP-1/2抑制剂，具有良好的细胞活性、对癌症的选择性超过正常细胞，以及口服生物利用度。在进入I期临床试验之前，尼拉帕尼在许多临床前模型中进行了表征，在I期临床试验中，它显示出适合每日一次口服给药的出色人体药代动力学，实现了PARP抑制的药效学目标，并对癌症患者具有有希望的活性。它目前正在进行3期临床试验，作为卵巢癌的维持治疗和乳腺癌的治疗。
Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP in the context of defects in other DNA repair mechanisms provide a tumor specific way to kill cancer cells. We describe the rationale for this approach and the design and discovery of niraparib, a potent PARP-1/2 inhibitor with good cell based activity, selectivity for cancer over normal cells, and oral bioavailability. Niraparib was characterized in a number of preclinical models before moving to phase I clinical trials, where it showed excellent human pharmacokinetics suitable for once a day oral dosing, achieved its pharmacodynamic target for PARP inhibition, and had promising activity in cancer patients. It is currently being tested in phase 3 clinical trials as maintenance therapy in ovarian cancer and as a treatment for breast cancer.