title: Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors.
abstract: Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure-activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.
authors.affiliation: Department of Neurology and Brain Science Institute, Johns Hopkins University, Baltimore, Maryland 21205, United States.
authors.forename: Krupa
authors.initials: K
authors.lastname: Shukla
authors.forename: Dana V
authors.initials: DV
authors.lastname: Ferraris
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Thomas
authors.forename: Marigo
authors.initials: M
authors.lastname: Stathis
authors.forename: Bridget
authors.initials: B
authors.lastname: Duvall
authors.forename: Greg
authors.initials: G
authors.lastname: Delahanty
authors.forename: Jesse
authors.initials: J
authors.lastname: Alt
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005972:Glutaminase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005972:Glutaminase