title: Structural basis for exploring the allosteric inhibition of human kidney type glutaminase.
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.
authors.affiliation: Department of Biological Sciences, National University of Singapore, 117543, Singapore.
authors.forename: Sarath
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Mechanobiology Institute Singapore, National University of Singapore, 117411, Singapore.
authors.forename: Catherine Qiurong
authors.initials: CQ
authors.lastname: Pan
authors.affiliation: Department of Neurology and Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Zimmermann
authors.affiliation: Department of Neurology and Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Duvall
authors.affiliation: Department of Neurology and Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Department of Biological Sciences, National University of Singapore, 117543, Singapore.|Mechanobiology Institute Singapore, National University of Singapore, 117411, Singapore.
authors.forename: Boon Chuan
authors.initials: BC
authors.lastname: Low
authors.affiliation: Department of Biological Sciences, National University of Singapore, 117543, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Sivaraman
mesh_terms: D000495:Allosteric Site; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000201:enzymology*; D007680:Kidney Neoplasms / Q000201:enzymology*; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D013440:Sulfides / Q000737:chemistry*; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005972:Glutaminase
keywords: BPTES; CB-839; allosteric inhibitors; cancer target; glutaminase