GSK2334470 is a potent and selective PDK1 (3-Phosphoinositide dependent protein kinase-1) inhibitor. GSK2334470 blocks the phosphorylation of known PDK1 substrates, but surprisingly find that the potency and kinetics of inhibition vary for different PDK1 targets. GSK2334470 subsequent activation of PDK1 substrates S6K1, SGK and RSK in HEK293, U87 and mouse embryonic fibroblast cell lines. GSK2334470 inhibited activation of an Akt1 mutant lacking the PH domain (pleckstrin homology domain) more potently than full-length Akt1, suggesting that GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2 (p90 ribosomal S6 kinase 2), another PDK1 target activated by the ERK (extracellular-signal-regulated kinase) pathway.
|Source||Oncogene (2014). Figure 2. GSK2334470|
|Incubation Time||7 days|
|Results||It is noteworthy that while administration of PDKi did not inhibit development of localized melanomas (local application of 4-HT), it reduced metastasis burden in lymph nodes as quantitated by S100 stain|
|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.
For a PDK1 inhibitor, the substrate matters.
Knight ZA. Biochem J. 2011 Jan 15;433(2):e1-2. PMID: 21175429.
Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1.
Najafov A, et al. Biochem J. 2011 Jan 15;433(2):357-69. PMID: 21087210.
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