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

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, whi...

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Published inOncotarget Vol. 7; no. 36; pp. 57943 - 57954
Main Authors Ramachandran, Sarath, Pan, Catherine Qiurong, Zimmermann, Sarah C, Duvall, Bridget, Tsukamoto, Takashi, Low, Boon Chuan, Sivaraman, J
Format Journal Article
LanguageEnglish
Published United States Impact Journals LLC 06.09.2016
Subjects
Allosteric Site
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation
Glutaminase - antagonists & inhibitors
Glutaminase - chemistry
HEK293 Cells
Humans
Inhibitory Concentration 50
Kidney - enzymology
Kidney Neoplasms - enzymology
Molecular Conformation
Protein Binding
Protein Conformation
Research Paper
Sulfides - chemistry
Thiadiazoles - chemistry
glutaminase
allosteric inhibitors
BPTES
cancer target
CB-839
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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.
AbstractList 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.
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 IC 50 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 1 S , 3 S -CBTBP and CB-839. We found that CB-839 produces a greater degree of interaction with cKGA than 1 S , 3 S -CBTBP or BPTES. The results of this study will facilitate the rational design of new KGA inhibitors to better treat glutamine-addicted cancers.
Author Ramachandran, Sarath
Sivaraman, J
Pan, Catherine Qiurong
Low, Boon Chuan
Zimmermann, Sarah C
Duvall, Bridget
Tsukamoto, Takashi
AuthorAffiliation 2 Mechanobiology Institute Singapore, National University of Singapore, 117411, Singapore
3 Department of Neurology and Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, USA
1 Department of Biological Sciences, National University of Singapore, 117543, Singapore
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Issue 36
Keywords glutaminase
allosteric inhibitors
BPTES
cancer target
CB-839
Language English
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Snippet Cancer cells employ glutaminolysis to provide a source of intermediates for their upregulated biosynthetic needs. Glutaminase, which catalyzes the conversion...
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crossref
pubmed
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Aggregation Database
Index Database
StartPage 57943
SubjectTerms Allosteric Site
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation
Glutaminase - antagonists & inhibitors
Glutaminase - chemistry
HEK293 Cells
Humans
Inhibitory Concentration 50
Kidney - enzymology
Kidney Neoplasms - enzymology
Molecular Conformation
Protein Binding
Protein Conformation
Research Paper
Sulfides - chemistry
Thiadiazoles - chemistry
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Title Structural basis for exploring the allosteric inhibition of human kidney type glutaminase
URI https://www.ncbi.nlm.nih.gov/pubmed/27462863
https://pubmed.ncbi.nlm.nih.gov/PMC5295402
Volume 7
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