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.

中文翻译：

---

发现2- [1-（4,4-二氟环己基）哌啶-4-基] -6-氟-3-氧代-2,3-二氢-1 H-异吲哚-4-羧酰胺（NMS-P118）：强大，口服有效且选择性强的PARP-1抑制剂，可用于癌症治疗

核蛋白聚（ADP-核糖）聚合酶-1（PARP-1）在DNA的信号传导和修复中具有公认的作用，并且是肿瘤学中的重要靶标，如通过临床试验中的非选择性候选物的数量所证明的那样同时针对PARP-1及其最接近的异构体PARP-2。我们计划的目标是找到一种PARP-1选择性抑制剂，该抑制剂可能减轻PARP-2交叉抑制所产生的毒性。因此，针对Nerviano医学科学（NMS）专有化学产品进行的HTS运动，然后进行SAR优化，使我们能够发现2- [1-（4,4-二氟环己基）哌啶4-4-基] -6-氟-3 -oxo-2,3-dihydro-1 H -isoindole-4-carboxamide（NMS- P118，20by）。NMS-P118被证明是一种有效的，口服可得的，高度选择性的PARP-1抑制剂，具有出色的ADME和药代动力学特征，在单药中以及与替莫唑胺联用在MDA-MB-436和Capan- 1个异种移植模型。具有PARP-1和PARP-2催化域蛋白的20by的共晶体结构使观察到的选择性合理化。