PF-4708671

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.