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BMN 673

Bing Wang, Daniel Chu, Ying Feng, Yuqiao Shen, Mika Aoyagi-Scharber, Leonard E Post
We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1...
January 14, 2016: Journal of Medicinal Chemistry
Ashleigh Herriott, Susan J Tudhope, Gesa Junge, Natalie Rodrigues, Miranda J Patterson, Laura Woodhouse, John Lunec, Jill E Hunter, Evan A Mulligan, Michael Cole, Lisa M Allinson, Jonathan P Wallis, Scott Marshall, Evelyn Wang, Nicola J Curtin, Elaine Willmore
In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors.We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 - 190052 pmol PAR/10⁶ cells) compared to that seen in healthy volunteer lymphocytes (2451 - 7519 pmol PAR/10⁶ cells)...
December 22, 2015: Oncotarget
Hiroyuki Seimiya
Poly(ADP-ribose) polymerases(PARP) synthesize the ADP-ribose polymers onto proteins and play a role in DNA repair. PARP inhibitors block the repair of single-strand breaks, which in turn gives rise to double-strand breaks during DNA replication. Thus, PARP inhibitors elicit synthetic lethality in cancer with BRCA1/2 loss-of-function mutations that hamper homologous recombination repair of double-strand breaks. Olaparib, the first-in-class PARP inhibitor, was approved for treatment of BRCA-mutated ovarian cancer in Europe and the United States in 2014...
August 2015: Nihon Rinsho. Japanese Journal of Clinical Medicine
Todd A Hopkins, Yan Shi, Luis E Rodriguez, Larry R Solomon, Cherrie K Donawho, Enrico L DiGiammarino, Sanjay C Panchal, Julie L Wilsbacher, Wenqing Gao, Amanda M Olson, DeAnne F Stolarik, Donald J Osterling, Eric F Johnson, David Maag
UNLABELLED: Poly(ADP-ribose) polymerases (PARP1, -2, and -3) play important roles in DNA damage repair. As such, a number of PARP inhibitors are undergoing clinical development as anticancer therapies, particularly in tumors with DNA repair deficits and in combination with DNA-damaging agents. Preclinical evidence indicates that PARP inhibitors potentiate the cytotoxicity of DNA alkylating agents. It has been proposed that a major mechanism underlying this activity is the allosteric trapping of PARP1 at DNA single-strand breaks during base excision repair; however, direct evidence of allostery has not been reported...
November 2015: Molecular Cancer Research: MCR
Jing Huang, Lei Wang, Zhongyi Cong, Zohreh Amoozgar, Evgeny Kiner, Deyin Xing, Sandra Orsulic, Ursula Matulonis, Michael S Goldberg
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...
August 7, 2015: Biochemical and Biophysical Research Communications
Alexandra-Zoe Andrei, Anita Hall, Alyssa L Smith, Claire Bascuñana, Abba Malina, Ashton Connor, Gulbeyaz Altinel-Omeroglu, Sidong Huang, Jerry Pelletier, David Huntsman, Steven Gallinger, Atilla Omeroglu, Peter Metrakos, George Zogopoulos
BRCA2-associated pancreatic ductal adenocarcinoma (PDAC) may be sensitive to agents that target homology-directed DNA repair, such as DNA crosslinking agents (DCLs) and PARP inhibitors (PARPis). Here, we assessed the sensitivities of BRCA2-deficient (Capan-1) and BRCA2-proficient (MIA PaCa-2) PDAC cell lines to a panel of DCLs and PARPis. Compared to MIA PaCa-2, Capan-1 was significantly more sensitive to all tested DCLs and PARPis, with similar increased sensitivities to cisplatin and the PARPi BMN 673 compared to other DCLs and the PARPi veliparib...
August 1, 2015: Cancer Letters
Malcolm A Smith, C Patrick Reynolds, Min H Kang, E Anders Kolb, Richard Gorlick, Hernan Carol, Richard B Lock, Stephen T Keir, John M Maris, Catherine A Billups, Dmitry Lyalin, Raushan T Kurmasheva, Peter J Houghton
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...
February 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Malcolm A Smith, Oliver A Hampton, C Patrick Reynolds, Min H Kang, John M Maris, Richard Gorlick, E Anders Kolb, Richard Lock, Hernan Carol, Stephen T Keir, Jianrong Wu, Raushan T Kurmasheva, David A Wheeler, Peter J Houghton
BACKGROUND: BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks. PROCEDURE: BMN 673 was tested in vitro at concentrations ranging from 0.1 nM to 1 μM and in vivo at a daily dose of 0.33 mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days...
January 2015: Pediatric Blood & Cancer
Mika Aoyagi-Scharber, Anna S Gardberg, Bryan K Yip, Bing Wang, Yuqiao Shen, Paul A Fitzpatrick
Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers. In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocket via an extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules...
September 2014: Acta Crystallographica. Section F, Structural Biology Communications
Junko Murai, Shar-Yin N Huang, Amèlie Renaud, Yiping Zhang, Jiuping Ji, Shunichi Takeda, Joel Morris, Beverly Teicher, James H Doroshow, Yves Pommier
Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacologic concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP-DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically modified chicken DT40 and human cancer cell lines...
February 2014: Molecular Cancer Therapeutics
Robert J Cardnell, Ying Feng, Lixia Diao, You-Hong Fan, Fatemah Masrorpour, Jing Wang, Yuqiao Shen, Gordon B Mills, John D Minna, John V Heymach, Lauren A Byers
PURPOSE: Small cell lung carcinoma (SCLC) is an aggressive malignancy affecting nearly 30,000 people annually in the United States. We have previously identified elevated PARP1 levels in SCLC and demonstrated in vitro sensitivity to the PARP inhibitors AZD 2281 and AG014699. Here, we evaluate activity of a novel, potent PARP inhibitor, BMN 673, and identify markers of response as a basis for developing predictive markers for clinical application. EXPERIMENTAL DESIGN: Inhibition of SCLC proliferation by BMN 673 was assayed in vitro and effects on tumor growth were measured in SCLC xenograft models...
November 15, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
S Postel-Vinay, I Bajrami, L Friboulet, R Elliott, Y Fontebasso, N Dorvault, K A Olaussen, F André, J-C Soria, C J Lord, A Ashworth
Excision repair cross-complementation group 1 (ERCC1) is a DNA repair enzyme that is frequently defective in non-small cell lung cancer (NSCLC). Although low ERCC1 expression correlates with platinum sensitivity, the clinical effectiveness of platinum therapy is limited, highlighting the need for alternative treatment strategies. To discover new mechanism-based therapeutic strategies for ERCC1-defective tumours, we performed high-throughput drug screens in an isogenic NSCLC model of ERCC1 deficiency and dissected the mechanism underlying ERCC1-selective effects by studying molecular biomarkers of tumour cell response...
November 21, 2013: Oncogene
Yuqiao Shen, Farah L Rehman, Ying Feng, Julia Boshuizen, Ilirjana Bajrami, Richard Elliott, Bing Wang, Christopher J Lord, Leonard E Post, Alan Ashworth
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...
September 15, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Meng-Fang Du, Xin-Ming Yin, Zhong-Jian Guo, Liang-Jun Zhu
Open reading frame 60 of Bombyx mori nucleopolyhedrovirus (Bm60) is located between 56,673 and 57,479 bp in the BmNPV genome which encodes 268 amino acid residues with predicted molecular weight of 31.0 kDa. Bm60 and its homologues have been identified in 11 completely sequenced lepidopteran NPVs. The transcript of Bm60 was detected by RT-PCR at 18-72 h post-infection (p.i.), while the corresponding protein could be detected at 24-72 h p.i. in BmNPV-infected BmN cells by Western blot analysis using a polyclonal antibody against Bm60...
November 30, 2006: Journal of Biochemistry and Molecular Biology
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