Research Papers:

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 and J. Sivaraman

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Oncotarget. 2016; 7:57943-57954. https://doi.org/10.18632/oncotarget.10791

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Sarath Ramachandran1, Catherine Qiurong Pan2, Sarah C. Zimmermann3, Bridget Duvall3, Takashi Tsukamoto3, Boon Chuan Low1,2, J. Sivaraman1

1Department of Biological Sciences, National University of Singapore, 117543, Singapore

2Mechanobiology Institute Singapore, National University of Singapore, 117411, Singapore

3Department of Neurology and Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, USA

Correspondence to:

J. Sivaraman, email: [email protected]

Keywords: glutaminase, cancer target, BPTES, CB-839, allosteric inhibitors

Received: November 30, 2015    Accepted: June 17, 2016    Published: July 22, 2016


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.

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