BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency

Y Shen, FL Rehman, Y Feng, J Boshuizen… - Clinical Cancer …, 2013 - AACR
Y Shen, FL Rehman, Y Feng, J Boshuizen, I Bajrami, R Elliott, B Wang, CJ Lord, LE Post…
Clinical Cancer Research, 2013AACR
Abstract 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
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
antitumor agents was evaluated both in vitro and in xenograft cancer models. Results: BMN …
Abstract
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 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 antitumor agents was evaluated both in vitro and in xenograft cancer models.
Results: BMN 673 is a potent PARP1/2 inhibitor (PARP1 IC50 = 0.57 nmol/L), but it does not inhibit other enzymes that we have tested. BMN 673 exhibits selective antitumor 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 more than 200-fold greater potency than existing PARP1/2 inhibitors. BMN 673 is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of BMN 673 elicited remarkable antitumor 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 antitumor 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. Clin Cancer Res; 19(18); 5003–15. ©2013 AACR.
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