Characterization 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

    Research output: Contribution to journalArticlepeer-review

    183 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)245-255
    Number of pages11
    JournalBiochemical Journal
    Volume431
    Early online date12 Aug 2010
    DOIs
    Publication statusPublished - 15 Oct 2010

    Keywords

    • Akt/protein kinase B (PKB)
    • Cancer
    • Kinase inhibitor
    • Phosphoinositide 3-kinase (PI3K)
    • p70 ribosomal S6 kinase (S6K)
    • Serum- and glucocorticoid-induced protein kinase (SGK)

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