Purpose: PARP1/2 inhibitors are a class of anticancer agents that target tumor-specific defects in DNA repair. Here, we describe BMN 673, a novel, highly potent PARP1/2 inhibitor with favorable metabolic stability, oral bioavailability and pharmacokinetic (PK) properties. Experimental Design: Potency and selectivity of BMN 673 was determined by biochemical assays. Anticancer activity either as a single-agent or in combination with other anti-tumor agents was evaluated both in vitro and in xenograft cancer models. Results: BMN 673 is a potent PARP1/2 inhibitor (PARP1 IC50 = 0.57 nM), but does not inhibit other enzymes we have tested. BMN 673 exhibits selective anti-tumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors (such as olaparib, rucaparib and veliparib). In vitro, BMN 673 selectively targeted tumor cells with BRCA1, BRCA2 or PTEN gene defects with 20- to >200-fold greater potency than existing PARP1/2 inhibitors. BMN 673 is readily orally bioavailable, with >40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of BMN 673 elicited remarkable anti-tumor activity in vivo; xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency were profoundly sensitive to oral BMN 673 treatment at well tolerated doses in mice. Synergistic or additive anti-tumor effects were also found when BMN 673 was combined with temozolomide, SN38 or platinum drugs. Conclusion: BMN 673 is currently in early phase clinical development and represents a promising PARP1/2 inhibitor with potentially advantageous features in its drug class.
- Received May 23, 2013.
- Accepted July 1, 2013.
- Copyright © 2013, American Association for Cancer Research.