| Description: |
Talazoparib tosylate (BMN 673ts) is a novel, potent and orally available PARP1/2 inhibitor with an IC50 of 0.57 nM for PARP1. |
| 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]. |
| 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 (KD) of 0.29 nM. Talazoparib inhibits PARP1 and -2 to a similar extent, with Kis 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]. |
| Cell Assay: |
LoVo cells are treated with Talazoparib (10, 40 nM) and temozolomide (TMZ) either alone or in combination for 5 days. Surviving fraction is determined using CellTiter-Glo assay.[1] |
| Animal Administration: |
Mice[1] In single-agent studies, olaparib (100 mg/kg), Talazoparib (0.33 or 0.1 mg/kg/d), or vehicle (10% DMAc, 6% Solutol, and 84% PBS) is administered by oral gavage (per os), once daily or Talazoparib (0.165 mg/kg) twice daily for 28 consecutive days. Mice are continuously monitored for 10 more days after last day of dosing[1]. |
| References: |
[1]. Shen Y, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013 Sep 15;19(18):5003-15. |
