CiteULike: Author Shpiro

The selectivity of protein kinase inhibitors: a further update.

J Bain — 2007-12-20T14:37:59-00:00

Biochem J, Vol. 408, No. 3. (15 December 2007), pp. 297-315.

The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70-80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)-raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.

Important role of the LKB1-AMPK pathway in suppressing tumourigenesis in PTEN deficient mice.

Xu Huang — 2008-05-09T20:36:26-00:00

The Biochemical journal (3 April 2008)

The LKB1 tumour suppressor phosphorylates and activates AMPK when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 kinase that is activated in the majority of human cancers. Blood glucose lowering type-2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In this study we investigated the importance of the LKB1-AMPK pathway in regulating tumourigenesis in mice resulting from deficiency of the PTEN tumour suppressor, which drives cell growth through over-activation of the Akt and mTOR kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumourigenesis on its own, but markedly accelerated tumour development in PTEN+/- mice. In contrast, activating the AMPK pathway by administration of PTEN+/- mice metformin, phenformin or A-769662, significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN deficient cells. Our findings highlight in an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumourigenesis resulting from loss of PTEN tumour suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1-pathway is activated. Most importantly our data demonstrate the potential of AMPK activators such as clinically approved metformin as anti-cancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.

Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis

Edward Mcmanus — 2005-03-24T21:43:02-00:00

The EMBO Journal, Vol. aop, No. current. (24 March 2005)