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

TY - JOUR

T1 - Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1)

AU - Pearce, Laura R.

AU - Alton, Gordon R.

AU - Richter, Daniel T.

AU - Kath, John C.

AU - Lingardo, Laura

AU - Chapman, Justin

AU - Hwang, Catherine

AU - Alessi, Dario R.

PY - 2010/10/15

Y1 - 2010/10/15

N2 - 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. P12-4708671. which specifically inhibits the S6K1 isoform with a K-1 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.

AB - 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. P12-4708671. which specifically inhibits the S6K1 isoform with a K-1 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.

KW - Akt/protein kinase B (PKB)

KW - Cancer

KW - Kinase inhibitor

KW - Phosphoinositide 3-kinase (PI3K)

KW - p70 ribosomal S6 kinase (S6K)

KW - Serum- and glucocorticoid-induced protein kinase (SGK)

U2 - 10.1042/BJ20101024

DO - 10.1042/BJ20101024

M3 - Article

C2 - 20704563

SN - 0264-6021

VL - 431

SP - 245

EP - 255

JO - Biochemical Journal

JF - Biochemical Journal

ER -