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.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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