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. Epub 2016 Mar 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzeneacetamides / chemistry
  • Benzeneacetamides / metabolism
  • Benzeneacetamides / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Glutaminase / antagonists & inhibitors*
  • Glutaminase / metabolism
  • Humans
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Sulfides / chemistry
  • Sulfides / metabolism
  • Sulfides / pharmacology*
  • Thiadiazoles / chemistry
  • Thiadiazoles / metabolism
  • Thiadiazoles / pharmacology*

Substances

  • Benzeneacetamides
  • CB-839
  • Enzyme Inhibitors
  • Sulfides
  • Thiadiazoles
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
  • Glutaminase