5WJ6

Crystal structure of glutaminase C in complex with inhibitor 2-phenyl-N-{5-[4-({5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}amino)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}acetamide (UPGL-00004)

Summary for 5WJ6

• Entry DOI: 10.2210/pdb5wj6/pdb
• Related: 5FI6
• Descriptor: Glutaminase kidney isoform, mitochondrial, 2-phenyl-N-{5-[4-({5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}amino)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}acetamide, ... (4 entities in total)
• Functional Keywords: glutaminase c, inhibitor, complex, glutamine, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 238773.42

Authors

Huang, Q.,Cerione, R.A. (deposition date: 2017-07-21, release date: 2018-01-10, Last modification date: 2023-10-04)

Primary citation

Huang, Q.,Stalnecker, C.,Zhang, C.,McDermott, L.A.,Iyer, P.,O'Neill, J.,Reimer, S.,Cerione, R.A.,Katt, W.P.
Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism.
J. Biol. Chem., 293:3535-3545, 2018

PubMed Abstract: Altered glycolytic flux in cancer cells (the "Warburg effect") causes their proliferation to rely upon elevated glutamine metabolism ("glutamine addiction"). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and therefore represents a potential therapeutic target. The small molecule CB-839 was reported to be more potent than other allosteric GAC inhibitors, including the parent compound bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl (BPTES), and is in clinical trials. Recently, we described the synthesis of BPTES analogs having distinct saturated heterocyclic cores as a replacement for the flexible chain moiety, with improved microsomal stability relative to CB-839 and BPTES. Here, we show that one of these new compounds, UPGL00004, like CB-839, more potently inhibits the enzymatic activity of GAC, compared with BPTES. We also compare the abilities of UPGL00004, CB-839, and BPTES to directly bind to recombinant GAC and demonstrate that UPGL00004 has a similar binding affinity as CB-839 for GAC. We also show that UPGL00004 potently inhibits the growth of triple-negative breast cancer cells, as well as tumor growth when combined with the anti-vascular endothelial growth factor antibody bevacizumab. Finally, we compare the X-ray crystal structures for UPGL00004 and CB-839 bound to GAC, verifying that UPGL00004 occupies the same binding site as CB-839 or BPTES and that all three inhibitors regulate the enzymatic activity of GAC via a similar allosteric mechanism. These results provide insights regarding the potency of these inhibitors that will be useful in designing novel small-molecules that target a key enzyme in cancer cell metabolism.

PubMed: 29317493
DOI: 10.1074/jbc.M117.810101

Experimental method

X-RAY DIFFRACTION (2.445 Å)