PF-477736 is a selective checkpoint kinase 1 (Chk1) inhibitor with Ki values of 0.49 nM and 47 nM for CHK1 and CHK2 respectively.A proprietary compound PF-477736 targets cell cycle checkpoint kinase 1 (chk1) with potential chemopotentiation activity.Chk1 inhibitor PF-477736 inhibits chk1, an ATP-dependent serine-threonine kinase that is a key component in the DNA replication-monitoring S/G2 checkpoint system.
Mol Cancer Res. 2022 Mar 1;20(3):456-467.
Chk1 Inhibition Potently Blocks STAT3 Tyrosine705 Phosphorylation, DNA-Binding Activity, and Activation of Downstream Targets in Human Multiple Myeloma Cells
PF-477736 purchased from AbMole
Sci Rep. 2017 Nov 14;7(1):15511.
Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer
PF-477736 purchased from AbMole
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Source | Sci Rep (2017). Figure 6. PF-477736 (Abmole Bioscience) |
| Method | i.p. | |
| Cell Lines | Xenograft mouse model | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 1–5 day | |
| Results | While vehicle-treated xenograft tumors derived from H-82 (Fig. 6D), H-526 (Fig. 6E) and H-69 (Fig. 6F) cells displayed a rapid growth, both VE-822 and PF-477736 treatment led to a massively delayed tumor growth in all three models, which was mimicked by a substantial reduction in Ki67 staining on histological examination in tumors that were excised following completion of treatment (Fig. 6G,H). |
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Source | Sci Rep (2017). Figure 5. PF-477736 (Abmole Bioscience) |
| Method | i.p. | |
| Cell Lines | Xenograft mouse model | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 1–5 day | |
| Results | While tumors displayed continuous growth in vehicle-treated animals, all tumors in the PF-477736-exposed cohort displayed a substantial volume reduction after completion of the second cycle |
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Source | Sci Rep (2017). Figure 4. PF-477736 (Abmole Bioscience) |
| Method | i.p. | |
| Cell Lines | Xenograft mouse model | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 1–5 day | |
| Results | Contrary to these substantial therapeutic effects inflicted by VE-822 and PF-477736 in SCLC-bearing animals, we only observed a minute survival extension in VE-822- and PF-477736-treated NSCLC-bearing mice. |
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Source | Sci Rep (2017). Figure 3. PF-477736 (Abmole Bioscience) |
| Method | Immunofluorescence | |
| Cell Lines | SCLC and NSCLC cells | |
| Concentrations | 1.0 μM | |
| Incubation Time | 48 h | |
| Results | Fully in line with our immunofluorescence data, SCLC cell lines displayed a significantly stronger γH2AX signal following VE-822 and PF-477736 treatment, than their NSCLC counterparts |
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Source | Sci Rep (2017). Figure 2. PF-477736 (Abmole Bioscience) |
| Method | Flow cytometry | |
| Cell Lines | SCLC and NSCLC cell | |
| Concentrations | 0.1 μM, 1.0 μM, 3.0 μM | |
| Incubation Time | 48 h | |
| Results | Of note, the slow growing cell line RP2 was less sensitive to VE-822 and PF-477736, compared to cell lines RP1, 3 and 4. The rapidly proliferating SCLC cell line RP5 displayed the most pronounced sensitivity to the cell cycle checkpoint abrogating agents VE-822 and PF-477736. |
| Cell Experiment | |
|---|---|
| Cell lines | p53-defective human cancer cell lines HT29 cells |
| Preparation method | IC50 MTT. The proliferation assays were done using an MTT assay. The IC50 assay measures the antiproliferative effects of PF-00477736 on p53-defective human cancer cell lines. Cells in each line were seeded in complete medium at an exponentially growing density in 96-well assay plate and allowed to attach for 16 h. Serial dilutions of PF-00477736 were then done, and appropriate controls were added to each plate. Cells were incubated with drug for 96 h. After incubation, MTT working stock diluted in complete medium was added to each well, and cells were incubated for 4 h. After centrifugation and supernatant removal, DMSO was added to each well and plates were read on SpectraMax plate reader at 540 nm. IC50 and PF50 results were calculated by concentration-response curve fitting using a Microsoft Excel–based four-variable analysis method. |
| Concentrations | 0, 180, 360 and 540 n M |
| Incubation time | 96 h |
| Animal Experiment | |
|---|---|
| Animal models | Colo205 cells tumour Xenograft Models in Athymic Nude Mice |
| Formulation | 50 nM sodium acetate buffer and 4% dextrose (pH 4) |
| Dosages | 4-60 mg/kg q3d × 4 |
| Administration | i.p. |
| Molecular Weight | 419.48 |
| Formula | C22H25N7O2 |
| CAS Number | 952021-60-2 |
| Solubility (25°C) | DMSO 40 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.
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Chk2-IN-1 (compound 1) is a potent and selective inhibitor of checkpoint kinase 2 (Chk2), with IC50s of 13.5 nM and 220.4 nM for Chk2 and Chk1, respectively. Chk2-IN-1 can elicit a strong ataxia telangiectasia mutated (ATM)-dependent Chk2-mediated radioprotection effect. |
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