Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1) (2024)

Pearce, L. R., Alton, G. R., Richter, D. T., Kath, J. C., Lingardo, L., Chapman, J., Hwang, C. (2010). Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochemical Journal, 431, 245-255. https://doi.org/10.1042/BJ20101024

Pearce, Laura R. ; Alton, Gordon R. ; Richter, Daniel T. et al. / Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). In: Biochemical Journal. 2010 ; Vol. 431. pp. 245-255.

@article{77b202a3e3994c98b2d8a664f9158066,

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

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.",

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)",

author = "Pearce, {Laura R.} and Alton, {Gordon R.} and Richter, {Daniel T.} and Kath, {John C.} and Laura Lingardo and Justin Chapman and Catherine Hwang and Alessi, {Dario R.}",

year = "2010",

month = oct,

day = "15",

doi = "10.1042/BJ20101024",

language = "English",

volume = "431",

pages = "245--255",

journal = "Biochemical Journal",

issn = "0264-6021",

publisher = "Portland Press",

}

Pearce, LR, Alton, GR, Richter, DT, Kath, JC, Lingardo, L, Chapman, J, Hwang, C 2010, 'Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1)', Biochemical Journal, vol. 431, pp. 245-255. https://doi.org/10.1042/BJ20101024

Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). / Pearce, Laura R.; Alton, Gordon R.; Richter, Daniel T. et al.
In: Biochemical Journal, Vol. 431, 15.10.2010, p. 245-255.

Research output: Contribution to journal › Article › peer-review

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 -

Pearce LR, Alton GR, Richter DT, Kath JC, Lingardo L, Chapman J et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochemical Journal. 2010 Oct 15;431:245-255. Epub 2010 Aug 12. doi: 10.1042/BJ20101024