Guy P A Vigers

Publications (5)15.85 Total impact

• Article: Discovery and SAR of spirochromane Akt inhibitors.

  Nicholas C Kallan, Keith L Spencer, James F Blake, Rui Xu, Justin Heizer, Josef R Bencsik, Ian S Mitchell, Susan L Gloor, Matthew Martinson, Tyler Risom, Stefan D Gross, Tony H Morales, Wen-I Wu, Guy P A Vigers, Barbara J Brandhuber, Nicholas J Skelton
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  ABSTRACT: A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.
  Bioorganic & medicinal chemistry letters 02/2011; 21(8):2410-4. · 2.65 Impact Factor
• Article: Discovery of spirocyclic sulfonamides as potent Akt inhibitors with exquisite selectivity against PKA.

  Rui Xu, Anna Banka, James F Blake, Ian S Mitchell, Eli M Wallace, Josef R Bencsik, Nicholas C Kallan, Keith L Spencer, Susan L Gloor, Matthew Martinson, Tyler Risom, Stefan D Gross, Tony H Morales, Wen-I Wu, Guy P A Vigers, Barbara J Brandhuber, Nicholas J Skelton
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  ABSTRACT: We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.
  Bioorganic & medicinal chemistry letters 02/2011; 21(8):2335-40. · 2.65 Impact Factor
• Article: Discovery of pyrrolopyrimidine inhibitors of Akt.

  James F Blake, Nicholas C Kallan, Dengming Xiao, Rui Xu, Josef R Bencsik, Nicholas J Skelton, Keith L Spencer, Ian S Mitchell, Richard D Woessner, Susan L Gloor, Tyler Risom, Stefan D Gross, Matthew Martinson, Tony H Morales, Guy P A Vigers, Barbara J Brandhuber
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  ABSTRACT: The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
  Bioorganic & medicinal chemistry letters 10/2010; 20(19):5607-12. · 2.65 Impact Factor
• Article: Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.

  Josef R Bencsik, Dengming Xiao, James F Blake, Nicholas C Kallan, Ian S Mitchell, Keith L Spencer, Rui Xu, Susan L Gloor, Matthew Martinson, Tyler Risom, Richard D Woessner, Faith Dizon, Wen-I Wu, Guy P A Vigers, Barbara J Brandhuber, Nicholas J Skelton, Wei Wei Prior, Lesley J Murray
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  ABSTRACT: Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.
  Bioorganic & medicinal chemistry letters 09/2010; 20(23):7037-41. · 2.65 Impact Factor
• Source

  Available from: arraybiopharma.com

  Article: Multiple active site corrections for docking and virtual screening.

  Guy P A Vigers, James P Rizzi
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  ABSTRACT: Several docking programs are now available that can reproduce the bound conformation of a ligand in an active site, for a wide variety of experimentally determined complexes. However, these programs generally perform less well at ranking multiple possible ligands in one site. Since accurate identification of potential ligands is a prerequisite for many aspects of structure-based drug design, this is a serious limitation. We have tested the ability of two docking programs, FlexX and Gold, to match ligands and active sites for multiple complexes. We show that none of the docking scores from either program are able to match consistently ligands and active sites in our tests. We propose a simple statistical correction, the multiple active site correction (MASC), which greatly ameliorates this problem. We have also tested the correction method against an extended set of 63 cocrystals and in a virtual screening experiment. In all cases, MASC significantly improves the results of the docking experiments.
  Journal of Medicinal Chemistry 02/2004; 47(1):80-9. · 5.25 Impact Factor