Characterisation of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1)

Laura R Pearce , Gordon R Alton , Daniel T Richter , John C Kath , Laura Lingardo , Justin Chapman , Catherine Hwang , Dario R Alessi (1)

1 MRC Protein Phosphorylation Unit, Department of Biochemistry

S6K1 is activated by insulin and growth factors via the PI3K and mTOR signalling pathways. S6K1 regulates numerous processes such as protein synthesis, growth, proliferation and longevity and its inhibition has been proposed as a strategy for the treatment of cancer and insulin resistance. Here we describe a novel cell-permeable inhibitor of S6K1, PF-4708671, 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 IGF1 while having no effect upon the TPA-induced phosphorylation of substrates of the highly related RSK and MSK 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. 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.

Mots clés: Life Sciences

Laura R Pearce, Gordon R Alton, Daniel T Richter, John C Kath, Laura Lingardo, et al.. Characterisation of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochemical Journal, 2010, 431 (2), pp.245-255. ⟨10.1042/BJ20101024⟩. ⟨hal-00521559⟩