Shen Yuqiao, Aoyagi-Scharber Mika, Wang Bing
BioMarin Pharmaceutical Inc., Novato, California
BioMarin Pharmaceutical Inc., Novato, California.
J Pharmacol Exp Ther. 2015 Jun;353(3):446-57. doi: 10.1124/jpet.114.222448. Epub 2015 Mar 10.
Recent findings indicate that a major mechanism by which poly(ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex "locks" onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they display similar capacity to inhibit PARP catalytic activity, their relative abilities to trap PARP differ by several orders of magnitude, with the ability to trap PARP closely correlating with each drug's ability to kill cancer cells. In this article, we review the available data on molecular interactions between these clinical-stage PARP inhibitors and PARP proteins, and discuss how their biologic differences might be explained by the trapping mechanism. We also discuss how to use the PARP-trapping mechanism to guide the development of PARP inhibitors as a new class of cancer therapy, both for single-agent and combination treatments.
最近的研究结果表明，聚（ADP-核糖）聚合酶（PARP）抑制剂杀死癌细胞的主要机制是将PARP1和PARP2捕获到DNA损伤位点。PARP酶-抑制剂复合物“锁定”在受损的DNA上，阻止DNA修复、复制和转录，从而导致细胞死亡。几种临床阶段的PARP抑制剂，包括维利帕尼、鲁卡帕尼、奥拉帕尼、尼拉帕尼和他拉唑帕尼，已经对其PARP捕获活性进行了评估。尽管它们显示出相似的抑制PARP催化活性的能力，但它们捕获PARP的相对能力相差几个数量级，捕获PARP的能力与每种药物杀死癌细胞的能力密切相关。在本文中，我们综述了这些临床阶段的PARP抑制剂与PARP蛋白之间分子相互作用的现有数据，并讨论了它们的生物学差异如何通过捕获机制来解释。我们还讨论了如何利用PARP捕获机制来指导PARP抑制剂作为一类新型癌症治疗药物的开发，包括单药治疗和联合治疗。
