Design, synthesis, and pharmacological evaluation of bis-2-(5- phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors

Krupa Shukla, Dana V. Ferraris, Ajit G. Thomas, Marigo Stathis, Bridget Duvall, Greg Delahanty, Jesse Alt, Rana Rais, Camilo Rojas, Ping Gao, Yan Xiang, Chi V. Dang, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)10551-10563
Number of pages13
JournalJournal of medicinal chemistry
Volume55
Issue number23
DOIs
StatePublished - Dec 13 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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