Advancements in Targeted Cancer Therapy: The Potential of NMS-P293, a Selective PARP-1 Inhibitor

Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in DNA repair and signaling, making it a significant target for cancer therapies. The synthetic lethality between PARP-1 inhibition and the loss of BRCA1/2 genes is a known phenomenon, leading to the development of PARP-1 inhibitors that selectively target tumor cells with DNA repair pathway deficiencies. However, current inhibitors also affect PARP-2, due to their structural similarity, which can lead to unwanted side effects.

The study introduces NMS-P293, a new and potent PARP-1 inhibitor with over 200 times more selectivity for PARP-1 than PARP-2. It effectively inhibits the synthesis of poly ADP-ribose (PAR) induced by hydrogen peroxide in cells, demonstrating its mechanism of action. NMS-P293 shows activity specifically against tumor cell lines with defects in homologous recombination (HR) repair, such as those with pTEN or BRCA mutations, while leaving cells with proficient DNA repair mechanisms and normal myelocytes unharmed.

Furthermore, NMS-P293 exhibits advantageous pharmacokinetic properties, including low efflux ratio, high metabolic stability across species, low clearance, and excellent oral bioavailability in both rodents and non-rodents. Oral dosing in mice with BRCA-mutated breast cancer xenografts led to complete tumor regression and cure.

The preclinical profile of NMS-P293 is highly favorable, positioning it as a promising candidate for further development in cancer treatment. The study was presented at the 107th Annual Meeting of the American Association for Cancer Research by Alessia Montagnoli et al., highlighting its potential as a novel, potent, and selective PARP-1 inhibitor with significant antitumor efficacy and tolerability.