Structural basis for exploring the allosteric inhibition of human kidney type glutaminase

Sarath Ramachandran, Catherine Qiurong Pan, Sarah C. Zimmermann, Bridget Duvall, Takashi Tsukamoto, Boon Chuan Low, J. Sivaraman

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer cells employ glutaminolysis to provide a source of intermediates for their upregulated biosynthetic needs. Glutaminase, which catalyzes the conversion of glutamine to glutamate, is gaining increasing attention as a potential drug target. Small-molecule inhibitors such as BPTES and CB-839, which target the allosteric site of glutaminase with high specificity, demonstrate immense promise as anti-tumor drugs. Here, we report the study of a new BPTES analog, N,N'-(5,5'-(trans-cyclohexane-1,3-diyl) bis(1,3,4-tiadiazole-5,2-diyl))bis(2-phenylacetamide) (trans-CBTBP), and compared its inhibitory effect against that of CB-839 and BPTES. We show that CB-839 has a 30- and 50-fold lower IC50 than trans-CBTBP and BPTES, respectively. To explore the structural basis for the differences in their inhibitory efficacy, we solved the complex structures of cKGA with 1S, 3S-CBTBP and CB-839. We found that CB-839 produces a greater degree of interaction with cKGA than 1S, 3S-CBTBP or BPTES. The results of this study will facilitate the rational design of new KGA inhibitors to better treat glutamine-addicted cancers.

Original languageEnglish (US)
Pages (from-to)57943-57954
Number of pages12
JournalOncotarget
Volume7
Issue number36
DOIs
StatePublished - 2016

Keywords

  • Allosteric inhibitors
  • BPTES
  • CB-839
  • Cancer target
  • Glutaminase

ASJC Scopus subject areas

  • Oncology

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