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BMN 673Potent PARP inhibitor

BMN 673

Catalog No. A4153
Size Price Stock Qty
10mM (in 1mL DMSO) $165.00 In stock
Evaluation Sample $28.00 In stock
10mg $250.00 In stock
50mg $650.00 In stock

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Sample solution is provided at 25 µL, 10mM.

Quality Control

Quality Control & MSDS

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Chemical structure

BMN 673

Related Biological Data

BMN 673

Related Biological Data

BMN 673

Biological Activity

BMN673 is a potent and selective inhibitor of PARP1,PARP2 with Ki of 1.2 and 0.9 nM, respectively .
Targets PARP          
IC50 0.58 nM          

Protocol

Kinase experiment [1]:

PARP enzyme assays

For PARP inhibitor Ki determination, enzyme assays were conducted in 96-well FlashPlate with 0.5 U PARP1 enzyme , 0.25x activated DNA, 0.2 mCi [3H] NAD, and 5 mmol/L cold NAD(Sigma) in a final volume of 50 mL reaction buffer containing 10% glycerol (v/v), 25 mmol/L HEPES, 12.5 mmol/L MgCl2, 50 mmol/L KCl, 1 mmol/L dithiothreitol (DTT), and 0.01% NP-40 (v/v), pH 7.6. Reactions were initiated by adding NAD to the PARP reaction mixture with or without inhibitors and incubated for 1 minute at room temperature. Fifty microliter of ice-cold 20% trichloroacetic acid (TCA) was then added to each well to stop the reaction. The plate was sealed and shaken for a further 120 minutes at room temperature, followed by centrifugation. Radioactive signal bound to the FlashPlate was determined using Top-Count. PARP1 Km was determined using Michaelis–Menten equation from various substrate concentrations (1–100 mmol/L NAD). Compound Ki was calculated from enzyme inhibition curve according to the formula: Ki ¼ IC50/[1þ (substrate)/Km]. Km for PARP2 enzyme and compound Ki were determined with the same assay protocol except 30 ng PARP2, 0.25x activated DNA, 0.2 mCi [3H] NAD, and 20 mmol/L cold NAD were used in the reaction for 30 minutes at room temperature.

Cell experiment [2]:

Cell lines

SCLC cell lines

Preparation method

Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

24 h-96 h

Applications

BMN 673 exhibits a potent inhibitory effect on a panel of 11 SCLC cell lines (IC50=1.7 to 15 nmol/L), which are all within clinically achievable ranges. In addition, sensitivity to BMN673 correlates to DNA repair protein expression and PI3K pathway activity.

Animal experiment [1]:

Animal models

Nude mice bearing established subcutaneous MX-1 tumor xenografts.

Dosage form

Oral gavage and twice daily for 28 consecutive days.

Application

BMN 673 inhibits the growth of MX-1 xenografts in mice, with 4 of 6 mice achieving a complete response. 0.33 and 0.1 mg/kg BMN 673 is well tolerated, with no animal lethality.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

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 Sep 15;19(18):5003-15.

2. 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 Nov 15;19(22):6322-8.

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Chemical Properties

Cas No. 1207456-01-6 SDF Download SDF
Chemical Name (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-1H-pyrido[4,3,2-de]phthalazin-3(2H)-one
Canonical SMILES FC1=CC2=N[C@@H](C(C=C3)=CC=C3F)[C@H](C4=NC=NN4C)C(NNC5=O)=C2C5=C1
Formula C19H14F2N6O M.Wt 380.35
Solubility Soluble in DMSO > 10 mM Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Background

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.