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.
|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 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|
|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.
PF-00477736 mediates checkpoint kinase 1 signaling pathway and potentiates docetaxel-induced efficacy in xenografts.
Zhang C, et al. Clin Cancer Res. 2009 Jul 15;15(14):4630-40. PMID: 19584159.
Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1.
Blasina A et al. Mol Cancer Ther. 2008 Aug;7(8):2394-404. PMID: 18723486.
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