Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold

Sarah C. Zimmermann, Emily F. Wolf, Andrew Luu, Ajit G. Thomas, Marigo Stathis, Brad Poore, Christopher Nguyen, Quy Hoa Le Thi, Camilo Rojas, Barbara Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticle

Abstract

A series of allosteric kidney-type glutaminase (GLS) inhibitors were designed and synthesized using 1,4-di(5-amino-1,3,4-thiadiazol-2-yl)butane as a core scaffold. A variety of modified phenylacetyl groups were incorporated into the 5-amino group of the two thiadiazole rings in an attempt to facilitate additional binding interactions with the allosteric binding site of GLS. Among the newly synthesized compounds, 4-hydroxy-N-[5-[4-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]-1,3,4-thiadiazol-2-yl]-benzeneacetamide, 2m, potently inhibited GLS with an IC50 value of 70 nM, although it did not exhibit time-dependency as seen with CB-839. Antiproliferative effects of 2m on human breast cancer lines will be also presented in comparison with those observed with CB-839.

Original languageEnglish (US)
Pages (from-to)520-524
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume7
Issue number5
DOIs
StatePublished - May 12 2016

Keywords

  • allosteric inhibition
  • cancer metabolism
  • Glutaminase

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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