Poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in signaling and repair of DNA single strand breaks. PARP-1 is a well-established target in cancer therapy, as testified by the number of marketed drugs applied in the treatment of breast and prostate cancer. A study from Gianluca Papeo discovered and identified an PARP-1 inhibitor, NMS-P515.

NMS-P515 is a potent, orally active and stereospecific PARP-1 inhibitor, with a Kd of 16 nM in cell-free assay and an IC50 of 27 nM in Hela cells. NMS-P515 also has potent anti-tumor activity.

The authors carried a series experiments both in vitro and in vivo.

In vitro, NMS-P515 demonstrated that it is moderately soluble at neutral pH, and is highly permeable with an excellent metabolic stability in vitro. It also has a high plasma protein binding. NMS-P515 modestly inhibited two P450 cytochrome isoforms (CYP-2D6 IC50: 0.60 μM; CYP-2B6 IC50: 4.90 μM).

Moreover, NMSP515 was then varified in vivo efficacy studies. Both as monotherapy and in combination, on subcutaneously implanted Capan-1 pancreatic (BRCA2-mutated) mouse xenografts. Thus, administration of NMS-P515 for 12 days (80 mg/kg, orally, once daily) effectively reduced the tumor growth (maximal tumor growth inhibition observed: 48%, maximum body weight loss: 6%). An even more pronounced effect (maximal tumor growth inhibition: 79%, maximum body weight loss: 17%), was observed when animals were treated with NMS-P515 (80 mg/kg, orally once daily for 12 days) in combination with temozolomide (80 mg/kg, IV once a day for 5 days started from day 3).

To conclude, NMS-P515 is a potent, orally active and stereospecific PARP-1 inhibitor with potent anti-tumor activity.

Papeo G, et al. Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515. ACS Med Chem Lett. 2019 Mar 13;10(4):534-538.