BMN 673

BMN673 is a potent and selective PARP1/2 inhibitor with Ki of 1.2 and 0.9 nM, respectively ¹. It had no effect on panels of 72 receptors, ion channels, and enzymes ¹. BMN673 showed IC50 value of 0.57 nM in enzymatic assay of PARP1 ¹. In in vitro assay, it exhibited greater potency than other existing PARP inhibitors, such as veliparib, rucaparib, and olaparib ². It is also much more potent at trapping PARP-DNA complexes than other PARP inhibitors ³.

BMN673 has shown anti-tumor activity both in vitro and in vivo. It inhibited proliferation of tumor cells and xenografts with defects in homologous recombination ¹. The combination of BMN673 and DNA-damaging agents demonstrated synergistic anti-tumor effects ¹. In addition, study showed that the expression levels of DNA repair proteins and status of PI3K pathway predict response to BMN673 in small cell lung cancer ⁴.

BMN673 is currently under investigation in multiple clinical trials for advanced solid tumors or hematological malignancies, either as monotherapy or in combination with other anti-tumor agents.

References:
1. Shen Y, Rehman FL, Feng Y et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res 2013; 19: 5003-5015.
2. Cardnell RJ, Byers LA. Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung Cancer--Response. Clin Cancer Res 2014; 20: 2237.
3. Murai J, Huang SY, Renaud A et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13: 433-443.
4. Cardnell RJ, Feng Y, Diao L et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res 2013; 19: 6322-6328.

PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia.[Pubmed:26539646]

Oncotarget. 2015 Dec 22;6(41):43978-91.

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/10(6) cells) compared to that seen in healthy volunteer lymphocytes (2451 - 7519 pmol PAR/10(6) cells). PARP activity was associated with PARP1 protein expression and endogenous PAR levels. PARP activity was not associated with p53 or ATM loss, Binet stage, IGHV mutational status or survival, but correlated with Bcl-2 and Rel A (an NF-kB subunit). Levels of 8-hydroxy-2'-deoxyguanosine in DNA (a marker of oxidative damage) were not associated with PAR levels or PARP activity. The potent PARP inhibitor, talazoparib (BMN 673), inhibited CD40L-stimulated proliferation of CLL cells at nM concentrations, independently of Binet stage or p53/ATM function.PARP activity is highly variable in CLL and correlates with stress-induced proteins. Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib.

Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent.[Pubmed:26652717]

J Med Chem. 2016 Jan 14;59(1):335-57.

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-te trahydro-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 = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.

Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer.[Pubmed:28002809]

Oncotarget. 2017 Jan 24;8(4):6057-6066.

PURPOSE: To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. EXPERIMENTAL DESIGN: The HR status of 12 OCCC cell lines was determined using RAD51/gammaH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry. RESULTS: A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 -9.4 (SD +/- 0.29) vs -8.1 (SD +/- 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases. CONCLUSIONS: A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by gammaH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs.