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

Abstract

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.

Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors

“…16–18 At the same time, attempts have been made to standardize in vitro assay technology and to characterize PARP inhibitors in terms of selectivity. 19,20 However, most PARP inhibitors have yet been profiled only against a handful of family members, rarely including any representative of the mono-ADP-ribosyltransferase subfamily. Therefore, a more comprehensive, comparative analysis of widely used PARP and tankyrase inhibitors was needed to facilitate interpretation of experimental effects of these compounds including off-target effects within the PARP family.…”

DNA repair targeted therapy: The past or future of cancer treatment?

“…More recently, Papeo et al developed a potent PARP1 selective inhibitor, NMS-P118 (Fig. 3) (Papeo et al, 2015). NMS-P118 has an excellent absorption, distribution, metabolism, and excretion profile and high in vivo efficacy as a single agent in triple negative breast cancer with a BRCA1 mutation and also in combination with temozolomide in BRCA2 deficient pancreatic cancer xenograft models.…”

The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models

“…Data are presented as percentage cell growth relative to untreated control. Cellular PF 50 (potentiation factor at 50% cell survival) was calculated as the ratio of the IC 50 for MMS alone versus MMS in combination with single concentrations of PARP inhibitors.…”

“…C, SRB assay to assess potentiality effects of AZD2461 on MMS in HeLa cells. D, clonogenic survival assay to assess single-agent activity of AZD2461 and olaparib and corresponding IC 50 inhibitor. This difference was statistically significant (P < 0.001) at day 55 (when the temozolomide group was culled); the effect between the combination groups (i.e., temozolomide plus olaparib or AZD2461) was not statistically significant either at day 55 (P ¼ 0.53) or when the study was stopped at day 73 (P ¼ 0.57).…”

“…Together, advances in both the ability to generate inhibitors with a particular PARP specificity profile, as has been suggested recently (50), along with an understanding of the biological roles of the different PARP family members, should provide the opportunity to generate inhibitors with an optimal PARP inhibitory profile to maximize antitumor activity and therapeutic index.…”