Publications by authors named "Symon G Erskine"

2 Publications

  • Page 1 of 1

Distinct concentration-dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis.

Cancer Res 2009 Sep 18;69(17):6969-77. Epub 2009 Aug 18.

GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.

Polo-like kinase 1 (Plk1) is a conserved serine/threonine kinase that plays an essential role in regulating the many processes involved in mitotic entry and progression. In humans, Plk1 is expressed primarily during late G(2) and M phases and, in conjunction with Cdk1/cyclin B1, acts as master regulatory kinases for the myriad protein substrates involved in mitosis. Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types. We have identified a potent, selective, reversible, ATP-competitive inhibitor of Plk1, GSK461364A, capable of inhibiting cell growth of most proliferating cancer cell lines tested. We observe distinct cell cycle effects of GSK461364A depending on the dose used. The predominant phenotype for cells treated with GSK461364A is prometaphase arrest with characteristic collapsed polar polo spindle. At high concentrations, GSK461364A delays mitotic entry in G(2) followed by gradual progression into terminal mitosis; in some cell lines, this correlates with decreased apoptosis. Cell culture growth inhibition by GSK461364A can be cytostatic or cytotoxic but leads to tumor regression in xenograft tumor models under proper dose scheduling. Finally, we describe pharmacodynamic biomarkers of GSK461364A activity (pHH3 and Plk1) that are currently being evaluated in human cancer clinical trials.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-0945DOI Listing
September 2009

Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase.

Bioorg Med Chem Lett 2005 May;15(9):2305-9

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.
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http://dx.doi.org/10.1016/j.bmcl.2005.03.003DOI Listing
May 2005