Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.10791
Title: Structural basis for exploring the allosteric inhibition of human kidney type glutaminase
Authors: Ramachandran, S 
Pan, C.Q 
Zimmermann, S.C
Duvall, B
Tsukamoto, T
Low, B.C 
Sivaraman, J 
Keywords: antineoplastic agent
bis 2 (5 phenylacetamido 1,3,4 thiadiazol 2 yl)ethyl sulfide
cb 839
enzyme inhibitor
glutaminase
kidney type glutaminase
n,n' [5,5' (cyclohexane 1,3 diyl)bis(1,3,4 tiadiazole 5,2 diyl)]bis(2 phenylacetamide)
unclassified drug
antineoplastic agent
bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
glutaminase
protein binding
sulfide
thiadiazole derivative
allosterism
Article
binding affinity
complex formation
concentration response
controlled study
crystal structure
drug mechanism
drug protein binding
drug structure
embryo
enzyme inhibition
human
human cell
IC50
structure analysis
allosteric site
antagonists and inhibitors
cell proliferation
chemistry
conformation
enzymology
HEK293 cell line
kidney
kidney tumor
protein conformation
Allosteric Site
Antineoplastic Agents
Cell Proliferation
Glutaminase
HEK293 Cells
Humans
Inhibitory Concentration 50
Kidney
Kidney Neoplasms
Molecular Conformation
Protein Binding
Protein Conformation
Sulfides
Thiadiazoles
Issue Date: 2016
Citation: Ramachandran, S, Pan, C.Q, Zimmermann, S.C, Duvall, B, Tsukamoto, T, Low, B.C, Sivaraman, J (2016). Structural basis for exploring the allosteric inhibition of human kidney type glutaminase. Oncotarget 7 (36) : 57943-57954. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.10791
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.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174108
ISSN: 19492553
DOI: 10.18632/oncotarget.10791
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