AG-014699 (PF-01367338, Rucaparib) is a PARP inhibitor with a Ki of 1.4 nM. AG-014699 is the phosphate salt of AG 014447 (CAS 283173-50-2) and has improved aqueous solubility. Poly (ADP-ribose) polymerases (PARPs) are activated by DNA single- and double-strand breaks and promote repair of DNA damage through the relaxation of chromatin and recruitment of other repair proteins. AG-014699 inactivates PARP activity in cells with homologous recombination DNA repair pathway mutations at LC50 values ranging from 1.3-5.5 μM. Radio-sensitization by AG-014699 is due to downstream inhibition of NF-κB activation, and independent of SSB repair inhibition. Although AG014699 can enhance response to some chemotherapeutic drugs via improved delivery, this does not apply to doxorubicin. PARP inhibitors may still be of use to counter doxorubicin toxicity.
 |
Source | Oncogene (2012). Figure 2. AG-014699 |
| Method | Cytotoxicity Assay | |
| Cell Lines | p65+/+ and p65−/− MEFs | |
| Concentrations | 0.1 μM | |
| Incubation Time | 48 h | |
| Results | Here we show that, co-incubation with either AG-014699, p65 siRNA or PARP-1 siRNA radio-sensitized p65+/+ MEFs 1.4-fold compared to mock-transfected cells treated with IR. Significantly, a combination of p65 siRNA and AG-014699 showed no further sensitization |
 |
Source | Oncogene (2012). Figure 1. AG-014699 |
| Method | Western blots | |
| Cell Lines | p65+/+ and p65−/− MEFs | |
| Concentrations | 0.1 μM | |
| Incubation Time | 48 h | |
| Results | Cells treated with AG-014699, or a combination of AG-014699 and p65 siRNA exhibited very low (< 5%) PARP activity |
| Cell Experiment | |
|---|---|
| Cell lines | LoVo and SW620 cells |
| Preparation method | We estimated cell growth inhibition in exponentially growing LoVo and SW620 cells in 96-well plates exposed to increasing concentrations of single-agent PARP inhibitor, temozolomide or topotecan, or combinations of temozolomide or topotecan with PARP inhibitor for 5 days before staining with sulforhodamine B as described previously (18). Cell growth, determined after subtraction of time 0 values, was expressed as a percentage of the relevant DMSO, cytotoxic drug, or PARP inhibitor alone control, as appropriate. GI50 (concentration of drug that inhibited growth by 50%) values were calculated from the computer-generated curves (GraphPad Software, Inc. San Diego CA). |
| Concentrations | 0~1000µM |
| Incubation time | 5 days |
| Animal Experiment | |
|---|---|
| Animal models | SW620 tumor xenografts |
| Formulation | saline |
| Dosages | 0.1, 1, 10mg/kg |
| Administration | oral |
| Molecular Weight | 421.36 |
| Formula | C19H18FN3O.H3PO4 |
| CAS Number | 459868-92-9 |
| Solubility (25°C) | DMSO ≥30 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
[3] Hunter et al. Oncogene. NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699.
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