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Talazoparib

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Chemical Structure| 1207456-01-6 同义名 : BMN-673;LT-673
CAS号 : 1207456-01-6
货号 : A570059
分子式 : C19H14F2N6O
纯度 : 99%+
分子量 : 380.35
MDL号 : MFCD22666357
存储条件：

粉末 Keep in dark place,Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 25 mg/mL(65.73 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+40% PEG300+water 2 mg/mL clear

PO 0.5% CMC-Na 45 mg/mL suspension

生物活性
靶点

  • PARP1

    PARP1, IC50:0.57 nM
描述 PARP1, also called as Poly(ADP-ribose) polymerase, is involved in the signaling of DNA damage. It can recognize and bind DNA single or double-strand breaks, thus possessing various cellular function, including regulation of apoptosis and chromosome stability, gene amplification and transcription, as well as cell division and differentiation. PARP-2 is the closest homolog of PARP1 (~62% similarity in catalytic domain) and compensates for PARP-1 activity in DNA single-strand break. BMN 673 is a potent PARP1/2 inhibitor with IC50 value of 0.57nM for PARP1 (measured by PARP1 enzyme activity). BMN673 showed EC50 value of 2.5nM for inhibition of cellular PAR synthesis in LoVo cells, IC50 value of 5nM for single-agent cytotoxicity of Capan-1 cell survival reduction and GI50 value of 3nM for Temozolomide potentiation assay in LoVo cells. BMN 673 selectivity inhibited BRCA-deficient cells and delivered a therapeutic window between BRCA-proficient and –deficient models at much lower concentrations compared with the other PARP inhibitor, veliparib, rucaparib and olaparib. BMN 673 possessed good pharmacodynamics, as a single oral administration of 1 mg/kg BMN 673 caused drastically decreased intratumoral PAR levels at 2 and 8 hours following drug administration with partial recovery observed at 24 hours after dosing. Oral administration of BMN 673 at dose of 0.33mg/kg, daily, for 28 days caused significant growth inhibition of MX-1 xenografts in mice[1]. BMN 673 showed ~100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as single agent than olaparib[2].
作用机制 BMN 673 is anchored to the nicotinamide-binding pocket of PARP and extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes.[3]
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
BR5FVB1-Akt 0.1-100 nM Growth Inhibition Assay 24/48/72 h inhibits cell proliferation dose dependently 26047697
BR5FVB1-Akt 0.1-100 nM Apoptosis Assay 72 h induces apoptosis 26047697
BT-12 Growth Inhibition Assay IC50> 1,000 nM 25263539
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.63mL

0.53mL

0.26mL

13.15mL

2.63mL

1.31mL

26.29mL

5.26mL

2.63mL
参考文献

[1]Shen Y, Rehman FL, 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]Murai J, Huang SY, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014 Feb;13(2):433-43.

[3]Aoyagi-Scharber M, Gardberg AS, et al. Structural basis for the inhibition of poly(ADP-ribose) polymerases 1 and 2 by BMN 673, a potent inhibitor derived from dihydropyridophthalazinone. Acta Crystallogr F Struct Biol Commun. 2014 Sep;70(Pt 9):1143-9.