生物活性

• 靶点	PARP1 IC50:0.57nM

• 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
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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

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• 动物研究
  剂量	Nude Mice: o.1 mg/kg, 0.33 mg/kg[1] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01042379	Breast Neoplasms ... more >> Breast Cancer Breast Tumors Collapse <<	Phase 2	Recruiting	-	-
  NCT03077607	Advanced Solid Tumors	Phase 1	Completed	-	Hungary ... more >> PRA Magyarorszag Kft, Fazis I-es Klinikai Farmakologiai Vizsgalohely Budapest, Hungary, 1077 Moldova, Republic of ARENSIA Exploratory Medicine Phase I Unit, PMSI Institute of Oncology Chisinau, Moldova, Republic of, MD2025 Poland Szpital LUX MED Warsaw, Poland, 02-801 Russian Federation I.M. Sechenov First Moscow State Medical University Moscow, Russian Federation, 119435 I.M. Sechenov First Moscow State Medical University Moscow, Russian Federation, 119991 "BioEq" LLC Saint-Petersburg, Russian Federation, 197342 State budget healthcare institution of Yaroslavl region "Regional clinical oncology hospital" Yaroslavl, Russian Federation, 150054 Collapse <<
  NCT03642132	Ovarian Cancer	Phase 3	Recruiting	May 18, 2026	-

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• 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.