R547 is a potent and selective ATP-competitive CDK inhibitor.In cell-free assays, R547 effectively inhibited CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1 (Ki = 1–3 nmol/L) and was inactive (Ki > 5,000 nmol/L) against a panel of >120 unrelated kinases. In vitro, R547 effectively inhibited the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s ≤ 0.60 μmol/L.
|Source||Oncogene (2012). Figure 6. R547|
|Cell Lines||p27−/− male mice|
|Incubation Time||13 day|
|Results||Strikingly, R547 reduced dysplasia (Figure 6D) and also modestly reduced ectopic mitoses but had no effect on progenitor mitoses that are distant or adjacent to phalloidin-marked apical membranes, respectively|
|Cell lines||human tumor cell lines HCT116, H460a, MDA-MB-435, DU145, LOX, and A549|
|Preparation method||Tetrazolium Dye Proliferation [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] Assay|
|Incubation time||48 h|
|Animal models||HCT116, H460a, MDA-MB-435, DU145, LOX, and A549|
|Formulation||Oral R547 was formulated as a suspension in Klucel LF/Tween 80, and i.v. R547 was formulated as a solution in hydroxylpropyl β-cyclodextrin, sodium hydroxide, and water for i.v. injection|
|Dosages||40 mg/kg daily oral dosing and 40 mg/kg i.v. once weekly|
|Administration||oral or i.v.|
|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.
Assessment of network perturbation amplitudes by applying high-throughput data to causal biological networks.
Martin et al. BMC Syst Biol. 2012 May 31;6:54. PMID: 22651900.
Constitutive Smad linker phosphorylation in melanoma: a mechanism of resistance to transforming growth factor-β-mediated growth inhibition.
Cohen-Solal et al. Pigment Cell Melanoma Res. 2011 Jun;24(3):512-24. PMID: 21477078.
In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials.
DePinto et al. Mol Cancer Ther. 2006 Nov;5(11):2644-58. PMID: 17121911.
Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity.
Chu et al. J Med Chem. 2006 Nov 2;49(22):6549-60. PMID: 17064073.
|Related CDK Products|
THZ2 (an analog of THZ1) is a potent and selective CDK7 inhibitor which overcomes the instability of THZ1 in vivo (IC50s: CDK7=13.9 nM; TNBC cells=10 nM).
LY-3177833 is a potent and selective inhibitor of CDC7 with IC50 of 3.3 nM.
Voruciclib (P1446A-05) is a protein kinase inhibitor specific for the cyclin-dependent kinase 4 (CDK4) with IC50s of 90nM, 25nM, and 22nM for CDK4-CyclinD1, CDK1-Cyclin B, and CDK9-Cyclin T, respectively.
CVT-313 is a potent and selective inhibitor of CDK2 that prevents neointimal proliferation, which has an IC50 of 0.5 microM in vitro.
ON123300 is a potent inhibitor of CDK4, with an IC50 of 3.8 nM, with little inhibitory activity against CDKs 1,2,5 and 8.
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