Kevin Taylor

Publications (2)10.05 Total impact

• Source

  Available from: PubMed Central

  Article: Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).

  Tatiana McHardy, John J Caldwell, Kwai-Ming Cheung, Lisa J Hunter, Kevin Taylor, Martin Rowlands, Ruth Ruddle, Alan Henley, Alexis de Haven Brandon, Melanie Valenti, Thomas G Davies, Lynsey Fazal, Lisa Seavers, Florence I Raynaud, Suzanne A Eccles, G Wynne Aherne, Michelle D Garrett, Ian Collins
  [show abstract] [hide abstract]
  ABSTRACT: Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.
  Journal of Medicinal Chemistry 02/2010; 53(5):2239-49. · 4.80 Impact Factor
• Article: Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration.

  John J Caldwell, Thomas G Davies, Alastair Donald, Tatiana McHardy, Martin G Rowlands, G Wynne Aherne, Lisa K Hunter, Kevin Taylor, Ruth Ruddle, Florence I Raynaud, Marcel Verdonk, Paul Workman, Michelle D Garrett, Ian Collins
  [show abstract] [hide abstract]
  ABSTRACT: Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.
  Journal of Medicinal Chemistry 05/2008; 51(7):2147-57. · 5.25 Impact Factor