PF-4708671 is a novel cell-permeable inhibitor of S6K1 (p70 ribosomal S6 kinase 1) which specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1, while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF-4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF-4708671 displays no effect on the activity of RSK and MSK in vivo. PF-4708671 exhibits no significant inhibition of S6K2 or other AGC kinases (e.g. Akt, PKA and ROCK) in vitro. PF-4708671 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR.
|Source||Front Neurol (2018). Figure 2. PF-4708671|
|Cell Lines||Lesion mice|
|Concentrations||50 mg/kg in 5 mL/kg volume|
|Incubation Time||1 h|
|Results||Cumulative analysis showed that the increase in immobility time produced by the 6-OHDA lesion was reverted by rapamycin, but not by PF-4708671|
|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.
|Solubility||DMSO 20 mg/mL|
Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1).
Pearce LR, et al. Biochem J. 2010 Oct 15;431(2):245-55. PMID: 20704563.
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