Talazoparib tosylate

Talazoparib tosylate (BMN 673ts) is a novel, potent and orally available PARP1/2 inhibitor with an IC₅₀ of 0.57 nM for PARP1. IC50 & Target: IC50: 0.57 nM (PARP1)^[1] In Vitro: Talazoparib is a potent PARP1/2 inhibitor (PARP1 IC₅₀=0.57 nM), it has no effect on PARG activity at concentrations up to 1 μM. Talazoparib binds to PARP1 with a dissociation constant (K_D) of 0.29 nM. Talazoparib inhibits PARP1 and -2 to a similar extent, with K_is of 1.20 and 0.85 nM, respectively. Talazoparib selectively targets tumor cells with BRCA1, BRCA2, or PTEN gene defects with 20- to more than 200-fold greater potency than existing PARP1/2 inhibitors. Talazoparib targets tumor cells with homologous recombination gene defects. Tumor models that are either BRCA1-deficient (MX-1 and SUM149) or BRCA2-deficient (Capan-1) are profoundly sensitive to Talazoparib. Talazoparib induces nuclear γ-H2AX foci at concentrations as low as 100 pM^[1]. In Vivo: Talazoparib is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of Talazoparib elicits remarkable antitumor activity; xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency are profoundly sensitive to oral Talazoparib treatment at well-tolerated doses in mice. Synergistic or additive antitumor effects are also found when Talazoparib is combined with temozolomide, SN38, or platinum drugs^[1].