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]
Talazoparib/他拉唑帕利 细胞实验
Cell Line
Concentration
Treated Time
Description
References
mouse embryonic stem cells
25 nM
6 days
To screen for mutants resistant to Talazoparib, identified Parp1 mutations causing resistance
Nat Commun. 2018 May 10;9(1):1849.
HeLa cells
1 µM
12 days
To screen for PARP1 mutants resistant to Talazoparib, identified PARP1 DNA-binding domain mutations causing resistance
Nat Commun. 2018 May 10;9(1):1849.
HCT116-p53WT
10-100 nM
48 h
To evaluate the effect of Talazoparib in combination with TAS102 on DNA damage in p53WT cells, results showed that the combination significantly increased the fluorescence intensity of DNA damage markers gH2AX and RAD51.
Cell Rep Med. 2024 Mar 19;5(3):101434.
HCT116-p53KO
10-100 nM
48 h
To evaluate the effect of Talazoparib in combination with TAS102 on DNA damage in p53KO cells, results showed that the combination significantly increased the fluorescence intensity of DNA damage markers gH2AX and RAD51.
Cell Rep Med. 2024 Mar 19;5(3):101434.
MCF-7
200 nM
0-48 h
To evaluate the effect of talazoparib on autophagy initiation factors, results showed significant increase in ATG3, ATG5, ATG7, and ATG16L1 levels
Br J Cancer. 2021 Mar;124(7):1260-1274.
MDA-MB-231
200 nM
24-48 h
To evaluate the effect of talazoparib on autophagy, results showed significant increase in endogenous LC3B punctae
Br J Cancer. 2021 Mar;124(7):1260-1274.
FaDu
8 nM
To evaluate the effect of Talazoparib on the proliferation of FaDu cells expressing H3K36M
Genes Dev. 2024 Feb 13;38(1-2):46-69.
HSC-2
8 nM
To evaluate the effect of Talazoparib on the proliferation of HSC-2 cells expressing H3K36M
Genes Dev. 2024 Feb 13;38(1-2):46-69.
Talazoparib/他拉唑帕利 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c nude mice
SUM149 cell xenograft model
Oral
0.66 mg/ml
3 days on, 4 days off
To evaluate the effect of PARP1 mutation on Talazoparib treatment, found that PARP1 mutation caused tumors to be unresponsive to Talazoparib
Nat Commun. 2018 May 10;9(1):1849.
Mice
HT29 tumor model
Oral
0.15 mg/kg
Once daily for 5 days, followed by 2 days off
To evaluate the anti-tumor efficacy of Talazoparib in combination with TAS102 in the HT29 tumor model, results showed that the combination significantly inhibited tumor growth and improved survival.
Cell Rep Med. 2024 Mar 19;5(3):101434.
SCID mice
MCF-7 xenograft tumour model
Oral
2 mg/kg
Every other day for 30 days
To evaluate the effect of talazoparib and chloroquine combination therapy on tumour volume, results showed significant reduction in tumour volume
Br J Cancer. 2021 Mar;124(7):1260-1274.
Mice
PDX models
Oral
0.33mg/kg
6 days on/1 day off for 28 days
To evaluate the in vivo response of the PARP inhibitor talazoparib in PDX models representing the CN-high/p53mut and MMRd subtypes. The results showed that two out of four CN-high models exhibited stable disease, while the other two showed significant tumor growth inhibition, and no significant tumor growth inhibition was observed in the MMRd models.
Genome Med. 2022 Jan 10;14(1):3
Mice
HNSCC xenograft model
Intraperitoneal injection
50 mg/kg
Once daily for the duration of the experiment
To evaluate the effect of Talazoparib on tumor burden in H3K36M HNSCC xenograft model
Genes Dev. 2024 Feb 13;38(1-2):46-69.
Mice
STAG2-mutant AML model
Oral
0.25 mg/kg
Once daily for 4 weeks
To evaluate the effect of Talazoparib on STAG2-mutant AML model, results showed that Talazoparib significantly reduced the burden of mutant cells.
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