tcsc3422 A-966492

A-966492 is a novel and potent inhibitor of PARP1 and PARP2 with K_i of 1 nM and 1.5 nM, respectively.

IC50 & Target: Ki: 1 nM (PARP1), 1.5 nM (PARP2)^[1]

In Vitro: A-966492 is one of the most potent PARP inhibitors. A-966492 displays excellent potency against the PARP-1 enzyme with a K_i of 1 nM and an EC₅₀ of 1 nM in a whole cell assay. A-966492 significantly enhances the efficacy of TMZ in a dose-dependent manner. In addition, A-966492 is orally bioavailable across multiple species, crosses the blood−brain barrier, and appears to distribute into tumor tissue. A-966492 represents a promising, structurally diverse benzimidazole analogue and is being further characterized preclinically^[1].

In Vivo: A-966492 demonstrates good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin. In addition, A-966492 has excellent pharmaceutical properties and has demonstrated in vivo efficacy in preclinical mouse tumor models in combination with TMZ and carboplatin, as well as single agent activity in a BRCA1-deficient MX-1 tumor model. A-966492 is further characterized in Sprague−Dawley rats, beagle dogs, and cynomolgus monkeys, with A-966492 demonstrating oral bioavailabilities of 34−72% and half-lives of 1.7−1.9 hours. In vivo, A-966492 demonstrates significant enhancement of the efficacy of TMZ in a murine B16F10 syngeneic melanoma model, with the A-966492 combination groups showing superior efficacy^[1].