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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 |
Appears in Collections: | Elements Staff Publications |
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