Discovery of 2‑[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro‑1H‑isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP‑1 Inhibitor for Cancer Therapy

The nuclear protein poly­(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)­piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.核蛋白多聚ADP核糖聚合酶-1（poly(ADP-ribose) polymerase-1, PARP-1）已被广泛证实其在DNA信号传导与修复过程中发挥关键作用，是肿瘤学领域的重要靶点。当前多项临床试验中的候选药物均非选择性靶向PARP-1及其最相近的同工型PARP-2，这一现状充分印证了其靶点价值。本研究的目标是开发PARP-1选择性抑制剂，以潜在减轻因交叉抑制PARP-2所引发的毒副作用。为此，研究团队首先针对自有Nerviano Medical Sciences（NMS）化合物库开展高通量筛选，随后通过构效关系优化，成功发现化合物2-[1-(4,4-二氟环己基)哌啶-4-基]-6-氟-3-氧代-2,3-二氢-1H-异吲哚-4-甲酰胺（NMS-P118, 20by）。实验证实，NMS-P118是一种强效、口服生物可利用且具有高度选择性的PARP-1抑制剂，具备优异的ADME（吸收、分布、代谢、排泄）特性与药代动力学表现；在MDA-MB-436与Capan-1异种移植模型中，该化合物分别以单药及与替莫唑胺联合给药的方式均展现出显著的体内抗肿瘤活性。通过解析20by与PARP-1、PARP-2催化结构域的共晶结构，研究团队阐明了该化合物所展现出的选择性机制。