BMN-673 8R,9S - CAS 1207456-00-5
Catalog number: 1207456-00-5
Category: Inhibitor
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BMN-673 is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity. PARP inhibitor BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by single-strand DNA breaks. BMN-673 has been proven to be highly active in mouse models of human cancer and also appears to be more selectively cytotoxic with a longer half-life and better bioavailability as compared to other compounds in development.
Talazoparib (8R,9S); (8R,9S)-BMN-673; BMN673 (8R,9S); BMN 673 (8R,9S)
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1.Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program.
Smith MA;Reynolds CP;Kang MH;Kolb EA;Gorlick R;Carol H;Lock RB;Keir ST;Maris JM;Billups CA;Lyalin D;Kurmasheva RT;Houghton PJ Clin Cancer Res. 2015 Feb 15;21(4):819-32. doi: 10.1158/1078-0432.CCR-14-2572. Epub 2014 Dec 10.
PURPOSE: ;Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan.;EXPERIMENTAL DESIGN: ;Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment.;RESULTS: ;In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively.
2.The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer.
Huang J;Wang L;Cong Z;Amoozgar Z;Kiner E;Xing D;Orsulic S;Matulonis U;Goldberg MS Biochem Biophys Res Commun. 2015 Aug 7;463(4):551-6. doi: 10.1016/j.bbrc.2015.05.083. Epub 2015 Jun 3.
Familial breast and ovarian cancer are often caused by inherited mutations of BRCA1. While current prognoses for such patients are rather poor, inhibition of poly-ADP ribose polymerase 1 (PARP1) induces synthetic lethality in cells that are defective in homologous recombination. BMN 673 is a potent PARP1 inhibitor that is being clinically evaluated for treatment of BRCA-mutant cancers. Using the Brca1-deficient murine epithelial ovarian cancer cell line BR5FVB1-Akt, we investigated whether the antitumor effects of BMN 673 extend beyond its known pro-apoptotic function. Administration of modest amounts of BMN 673 greatly improved the survival of mice bearing subcutaneous or intraperitoneal tumors. We thus hypothesized that BMN 673 may influence the composition and function of immune cells in the tumor microenvironment. Indeed, BMN 673 significantly increases the number of peritoneal CD8(+) T cells and NK cells as well as their production of IFN-γ and TNF-α. These data suggest that the cell stress caused by BMN 673 induces not only cancer cell-intrinsic apoptosis but also cancer cell-extrinsic antitumor immune effects in a syngeneic murine model of ovarian cancer. BMN 673 may therefore serve as a promising adjuvant therapy to immunotherapy to achieve durable responses among patients whose tumors harbor defects in homologous recombination.
3.Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP.
Yokoyama T;Kohn EC;Brill E;Lee JM Int J Oncol. 2017 Mar 15. doi: 10.3892/ijo.2017.3914. [Epub ahead of print]
The aim of our study was to evaluate possible synergistic cytotoxic effects of the combination treatment with the BH3-mimetic ABT-263 and the PARP inhibitor BMN 673 in high-grade serous ovarian cancer (HGSOC) cells using clinically achievable concentrations of each drug. In vitro cytotoxic effects of ABT-263 and BMN 673 were assessed by XTT assay in three HGSOC cell lines: OVCAR3, OVCAR8, and OV90 cells. Combination index values and synergy/antagonism volumes were used to determine synergy. The drug effects on DNA damage accumulation, cell cycle progression, apoptosis induction, and expression levels of Bcl-2 family proteins were examined to dissect molecular mechanisms. The combination treatment synergistically decreased cell viability in a concentration- and time-dependent manner in all cell lines; combination index values were <0.9 and synergy/antagonism volumes were >100 after 72 h of treatment. Clinically achievable concentrations of ABT-263 2 µM and BMN 673 25 nM were used to investigate mechanisms. No increase in γ-H2AX foci formation was observed with addition of ABT-263 to BMN 673 treatment. The combination treatment increased the sub-G1 and Annexin V-positive cell populations after 48 h compared with the control and each monotherapy.
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CAS 1207456-00-5 BMN-673 8R,9S

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