ABT-888 (Veliparib) is a potent inhibitor of PARP-1 and PARP-2 with Ki values of 5.2nM and 2.9nM respectively. ABT-888 (Veliparib) inhibits PARPs, thereby inhibiting DNA repair and potentiating the cytotoxicity of DNA-damaging agents. ABT-888 (Veliparib) has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic.
|Source||Invest New Drugs (2013). Figure 4. ABT-888|
|Method||Annexin V apoptosis assay|
|Cell Lines||HCT-116 cells|
|Incubation Time||4 h, 24 h or 48 h|
|Results||Although little apoptosis was detected at the 24 h time point, a significant increase in apoptosis was observed at 48 h in the presence of SN38 or SN38 plus ABT-888 for both cell lines indicating that γH2AX preceded drug-inducedapoptosis.|
|Source||Invest New Drugs (2013). Figure 1. ABT-888|
|Method||PARP inhibition assay|
|Cell Lines||HCT-116 cells|
|Incubation Time||24 h|
|Results||To demonstrate that this change in activity was not due to altered protein expression, western blot analysis was performed on samples treated for 1 h or 24 h with 0.5 μM ABT-888, 10 nM SN38 or combinations of these two|
|Cell lines||C41 cells|
|Preparation method||Cellular PARP Assay. C41 cells were treated with test compound for 30 min in a 96-well plate. PARP was activated by damaging DNA with 1 mM H2O2 for 10 min. Cells were washed with ice-cold PBS once and fixed with prechilled methanol/acetone (7:3) at -20 °C for 10 min. After air-drying, plates were rehydrated with PBS and blocked using 5% nonfat dry milk in PBS-tween (0.05%) (blocking solution) for 30 min at room temperature. Cells were incubated with anti-PAR antibody 10H (1:50) in blocking solution at room temperature for 60 min followed by washing with PBS-Tween20 5 times and incubation with goat antimouse fluorescein 5(6)-isothiocyanate (FITC)-coupled antibody (1:50) and 1 µg/mL 4′,6-diamidino-2-phenylindole (DAPI) in blocking solution at room temperature for 60 min. After washing with PBS-Tween20 5 times, analysis was performed using an fmax Fluorescence Microplate Reader set at the excitation and emission wavelength for FITC or the excitation and emission wavelength for DAPI. PARP activity (FITC signal) was normalized with cell numbers (DAPI).|
|Incubation time||30 min|
|Animal models||MX-1 Tumor Model|
|Formulation||2.5% EtOH, 1 drop TW-80, 25% PEG400, PBS|
|Dosages||12.5mg/kg, BID, P6-11|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥45 mg/mL|
Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas.
Kummar et al. Cancer Res. 2011 Sep 1;71(17):5626-34. PMID: 21795476.
The poly(ADP-Ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy.
Nowsheen et al. Radiother Oncol. 2011 Jun;99(3):331-8. PMID: 21719137.
|Related PARP Products|
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Niraparib (MK-4827) tosylate is an excellent PARP1 and PARP2 inhibitor with IC50 of 3.8 and 2.1 nM, respectively.
Daidzein is an inactive analogue of genistein, a tyrosine kinase inhibitor and an estrogen receptor activator.
NMS-P118 is a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles, showing 150-fold selectivity for PARP-1 over PARP-2 (Kd 0.009 μM vs 1.39 μM, respectively).
E7449 is an orally bioavailable, brain penetrable, small molecule dual inhibitor of PARP1/2 that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1/2), important regulators of canonical Wnt/β-catenin signaling. It has IC50 values of 1.0 and 1.2 nM for PARP1 and 2, respectively.
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