2. Academic Validation
  3. Design and evaluation of novel glutaminase inhibitors

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

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: lam179@pitt.edu.
  • 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.

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