NMS-P293 is a novel, potent and selective small molecule inhibitor of poly (ADP-ribose) polymerase (PARP-1 Kd = 2 nM).
NMS-P293 inhibits the poly-ADP ribosylation (PAR) induced by DNA damage, leading to the inability of homologous repair deficient (HRD) tumor cells to repair damage and to apoptotic death, while sparing normal cells.
NMS-P293 significantly differs from other PARP inhibitors in several respects. Firstly, while possessing potent in vitro and in vivo efficacy in HRD tumors (e.g. BRCA, PTEN loss), it does not induce “DNA trapping”, i.e. the formation of PARP-chromatin complexes. Secondly, NMS-293 is not a substrate of PgP mediated drug efflux, believed to be a mechanism of resistance to current PARP inhibitors. Finally, NMS-P293 extensively crosses the blood brain barrier in rats and mice, with a brain/plasma ratio of 4-10, significantly higher than that of major comparators and opening the potential for treating primary brain tumors and brain metastasis with PARP inhibitor therapy. Extensive preclinical profiling revealed that NMS-P293 possesses favourable drug-like characteristics, which include high in vitro cross-species metabolic stability, lack of cytochrome interaction, and excellent pharmacokinetic profile, with low clearance and nearly complete oral bioavailability in both rodents and non rodents. Preclinical efficacy and PK/PD studies were conducted to assess the mechanism of action of NMS-P293 in an HRD setting, the MDA-MD-436 (BRCA1 mutant) human breast cancer xenograft model. Inhibition of PAR was observed in tumors following single oral administration of 50 mg/kg NMS-P293, with a > 95% decrease of this biomarker persisting for > 24 h. Inverse correlation was observed between intratumoral PAR levels and NMS-P293 concentrations in plasma and in tumor. Significantly, levels of NMS-P293 in tumor were consistently higher (> 3.5-fold) than in plasma, with an intratumoral concentration of > 2 μM at 24 h, in line with the prolonged PAR inhibition. In agreement with these PD effects, NMS-P293, orally administered as single agent, induced potent dose-related growth inhibition of BRCA mutated tumor model, with cured animals. Furthermore, NMS-P293 also possesses potent synergistic efficacy and tolerability in combination with temozolomide (TMZ) in glioblastoma (GBM) tumor models, including TMZ resistant MGMT hypomethylated GBMs.
The unique preclinical features of NMS-P293, which includes a highly permissive profile in GLP drug safety studies, render this compound an appealing candidate for clinical development, both as a single agent and in drug combination therapy regimes.
Citation Format: Alessia Montagnoli, Gianluca Papeo, Sonia Rainoldi, Francesco Caprera, Marina Ciomei, Eduard Felder, Daniele Donati, Antonella Isacchi, Arturo Galvani. NMS-P293, a PARP-1 selective inhibitor with no trapping activity and high CNS penetration, possesses potent in vivo efficacy and represents a novel therapeutic option for brain localized metastases and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4843.