title: Design and evaluation of novel glutaminase inhibitors.
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.
authors.affiliation: 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.
authors.forename: Lee A
authors.initials: LA
authors.lastname: McDermott
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA; University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15261, USA.
authors.forename: Prema
authors.initials: P
authors.lastname: Iyer
authors.affiliation: University of Pittsburgh, Drug Discovery Institute, Pittsburgh, PA 15261, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Vernetti
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Rimer
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Jingran
authors.initials: J
authors.lastname: Sun
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Boby
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Yang
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Fioravanti
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: O'Neill
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.affiliation: University of Pittsburgh, Department of Pharmaceutical Sciences, Pittsburgh, PA 15261, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Drakes
authors.affiliation: Cornell University, Department of Molecular Medicine, Ithaca, NY 14853, USA.
authors.forename: William
authors.initials: W
authors.lastname: Katt
authors.affiliation: Cornell University, Laboratory for Accelerator-based Sciences and Education, Ithaca, NY 14853, USA.
authors.forename: Qingqiu
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Cornell University, Department of Molecular Medicine, Ithaca, NY 14853, USA; Cornell University, Department of Chemistry and Chemical Biology, Ithaca, NY 14853, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Cerione
mesh_terms: D044482:Benzeneacetamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013830:Thiadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D044482:Benzeneacetamides; C000593334:CB-839; D004791:Enzyme Inhibitors; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005972:Glutaminase
keywords: BPTES; CB-839; GAC; Novel glutaminase inhibitors