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. 2013 Sep 15;19(18):5003-15.
doi: 10.1158/1078-0432.CCR-13-1391. Epub 2013 Jul 23.

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

Yuqiao Shen  1 , Farah L Rehman, Ying Feng, Julia Boshuizen, Ilirjana Bajrami, Richard Elliott, Bing Wang, Christopher J Lord, Leonard E Post, Alan Ashworth
Affiliations

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

Yuqiao Shen et al. Clin Cancer Res. .

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.

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Figures

Figure 1
Figure 1. BMN 673 is a potent PARP inhibitor
A) Structure and PARP1 IC50 of BMN 673, its corresponding isomer LT-00674, and the racemic mixture LT-00628. B) Biacore T200 sensorgrams of BMN 673 and Veliparib binding to immobilized recombinant human PARP1. Top: BMN 673 binding sensorgram, bottom: veliparib. Each compound was injected at increasing concentrations (12.5, 25, 50, 100, 200 nM, 60 sec per injection) over a chip surface that was pre-coated with recombinant PARP1. The on-rates, off-rates and dissociation constants (KD) were determined as described in Materials and Methods.
Figure 2
Figure 2
A) siRNA targeting HR genes sensitize to PARP1/2 inhibitors. CAL51 cells were transfected with a library of siRNAs and treated with BMN 673, olaparib, veliparib or rucaparib. Each drug was used at its respective SF80 concentration. The effect of each siRNA on drug sensitization was quantified by the calculation of a Drug Effect (DE) Z score. Out of 960 genes, those involved in HR-mediated DNA repair were a prominent feature of the sensitivity profile of all PARP1/2 inhibitors. DE Z scores for BRCA1 BRCA2, ATM, FANCM, RAD51 and PALB2 are shown here. (B and C) BMN 673 is selectively toxic to BRCA1 or BRCA2 deficient cells. Dose response curves from clonogenic survival assays in a variety of isogenic models are shown. The response of BRCA1 deficient and proficient ES cells (generated by gene targeting) are shown as are the responses in human DLD1 tumor cell lines with BRCA2 gene targeted alleles. Cells were exposed to different PARP1/2 inhibitors as shown for 10-14 days, after which surviving colonies were counted and Surviving Fractions calculated by normalizing surviving colony numbers to colony numbers in control (vehicle-treated) cells.
Figure 3
Figure 3. BMN 673 exhibits anti-tumor activity against a BRCA mutant tumor model in mice
A) MX-1 human mammary xenografts were inoculated subcutaneously in female athymic nu/nu mice. When tumors reached an average volume of ~150 mm3 (range 100-196 mm3), mice were randomized into various treatment groups, and were treated orally, once-daily for 28 consecutive days, with BMN 673 (0.33 or 0.1 mg/kg/day), olaparib (100 mg/kg/day) or empty vehicle. Median tumor volume was plotted against days of treatment (first day of treatment is defined at Day1). B) Inhibition of PARP activity by a single oral dose of BMN 673 (1 mg/kg) was demonstrated ex vivo by measuring MX-1 tumor PAR levels at 2, 8 hours and the inhibition was partially recovered 24 hours after dosing. Intratumoral PARP inhibition was also observed with olaparib at 100 mg/kg oral administration, but the effect was much shorter. Each bar represents an individual tumor from an individual animal. C) BMN 673 is more effective in mouse xenograft models with 0.165mg/kg/dose twice-a-day dosing than 0.33 mg/kg/dose once-a-day dosing. In the MX-1 model, not only did all 6 mice treated with 0.165mg/kg/dose 2X/day regimen reached complete response, but also none of the mice had tumor re-growth until the end of the study, eight weeks after BMN 673 dosing stopped. Median tumor volume was plotted against days of treatment (first day of treatment is defined at Day1).
Figure 4
Figure 4. BMN 673 potentiates the effects of DNA-damaging cytotoxic agents
A) LoVo cells were treated with BMN 673 and temozolomide either alone or in combination for 5 days. Surviving fraction was determined using CellTiterGlo assay. BMN 673 significantly increased the cytotoxicity of temozolomide in LoVo cells. B) BMN 673 sensitized MX-1 cells to SN-38 cytotoxicity in a dose dependent fashion. C) Nude mice carrying MX-1 tumor xenografts were treated with oral administration of BMN 673, olaparib, or vehicle once-a-day from day 1 to 8. Cisplatin was dosed intraperitoneally at 6 mg/kg on the third day of PARP inhibitor treatment. While 0.1, 0.33 and 1 mg/kg of BMN 673 showed dose-dependent sensitization of the cisplatin, 100 mg/kg olaparib showed a sensitizing effect that is equivalent to the lowest dose of BMN 673. D) Once-a-day dosing of BMN 673 for 8 days potentiated carboplatin more than 5 daily dosing, which in turn generated tumor growth inhibition more than carboplatin alone. BMN 673 was dosed orally, once-a-day for either 5 or 8 days starting on Day 1, at a dosage level of 0.33 mg/kg. Carboplatin at a dosage of 35 mg/kg or its vehicle (saline) for the control group was administered intraperitoneally on Day 1, half an hour after BMN 673 administration. Median tumor volume was plotted against days of treatment (first day of treatment is defined at Day 1).
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