Design and evaluation of novel glutaminase inhibitors

  • Bioorg Med Chem. 2016 Apr 15;24(8):1819-39. doi: 10.1016/j.bmc.2016.03.009.
Lee A McDermott  1 ,  Prema Iyer  2 ,  Larry Vernetti  3 ,  Shawn Rimer  4 ,  Jingran Sun  4 ,  Melissa Boby  4 ,  Tianyi Yang  4 ,  Michael Fioravanti  4 ,  Jason O'Neill  4 ,  Liwei Wang  4 ,  Dylan Drakes  4 ,  William Katt  5 ,  Qingqiu Huang  6 ,  Richard Cerione  7
Affiliations
  • 1. University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA; University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15261, USA. Electronic address: [email protected].
  • 2. University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA; University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15261, USA.
  • 3. University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15261, USA.
  • 4. University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
  • 5. Cornell University, Department of Molecular Medicine, Ithaca, NY 14853, USA.
  • 6. Cornell University, Laboratory for Accelerator-based Sciences and Education, Ithaca, NY 14853, USA.
  • 7. Cornell University, Department of Molecular Medicine, Ithaca, NY 14853, USA; Cornell University, Department of Chemistry and Chemical Biology, Ithaca, NY 14853, USA.
PMID: 26988803 DOI: 10.1016/j.bmc.2016.03.009
Abstract

A novel set of GAC (kidney Glutaminase isoform C) inhibitors able to inhibit the enzymatic activity of GAC and the growth of the triple negative MDA-MB-231 breast Cancer cells with low nanomolar potency is described. Compounds in this series have a reduced number of rotatable bonds, improved ClogPs, microsomal stability and ligand efficiency when compared to the leading GAC inhibitors BPTES and CB-839. Property improvements were achieved by the replacement of the flexible n-diethylthio or the n-butyl moiety present in the leading inhibitors by heteroatom substituted heterocycloalkanes.

Keywords
BPTES; CB-839; GAC; Novel glutaminase inhibitors.