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

LR Pearce, GR Alton, DT Richter, JC Kath… - Biochemical …, 2010 - portlandpress.com
LR Pearce, GR Alton, DT Richter, JC Kath, L Lingardo, J Chapman, C Hwang, DR Alessi
Biochemical Journal, 2010portlandpress.com
S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K
(phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) 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. In the present paper we describe a novel cell-
permeable inhibitor of S6K1, PF-4708671, which specifically inhibits the S6K1 isoform with a …
S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) 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. In the present paper 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 IGF-1 (insulin-like growth factor 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 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR.
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