TY - JOUR
T1 - Structural basis for exploring the allosteric inhibition of human kidney type glutaminase
AU - Ramachandran, Sarath
AU - Pan, Catherine Qiurong
AU - Zimmermann, Sarah C.
AU - Duvall, Bridget
AU - Tsukamoto, Takashi
AU - Low, Boon Chuan
AU - Sivaraman, J.
N1 - Funding Information:
This work was supported by Ministry of Education (MoE) Singapore Tier-2 grant R154-000-625-112. SCZ is an NIH postdoctoral fellow (F32CA200278). SR is a graduate scholar in receipt of a research scholarship from the National University of Singapore (NUS).
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Allosteric inhibitors
KW - BPTES
KW - CB-839
KW - Cancer target
KW - Glutaminase
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U2 - 10.18632/oncotarget.10791
DO - 10.18632/oncotarget.10791
M3 - Article
C2 - 27462863
AN - SCOPUS:84988373695
SN - 1949-2553
VL - 7
SP - 57943
EP - 57954
JO - Oncotarget
JF - Oncotarget
IS - 36
ER -