UPGL00004 is a Potent Allosteric and Orally Active Glutaminase C Inhibitor

The Warburg effect in cancer cells refers to the significant alteration of the glycolytic pathway. It increases the generation of lactate, decreases mitochondrial metabolism of pyruvate, and accompanying with the reduction in oxidative phosphorylation. The Warburg effect has a significant consequence. Cancer cells need to develop alternative mechanisms that provide inputs into the citric acid cycle. One of the most common of these mechanisms results in an addiction to glutamine. It is an amino acid that is abundant in the bloodstream. Glutaminase C (GAC) is a 65-kDa enzyme composed of 598 residues. GAC primarily exists as either a dimer or a tetramer. The dimer is inactive, whereas the tetramer has catalytic activity. Because GAC is a gatekeeper for cellular metabolism, its activity is critical to the survival of many types of cancer cells. UPGL00004 is a potent allosteric GAC inhibitor (IC50=29 nM).

UPGL00004 is a Potent Allosteric and Orally Active Glutaminase C Inhibitor 2019 09 16 - UPGL00004 is a Potent Allosteric and Orally Active Glutaminase C Inhibitor

UPGL00004 occupies the same binding site as CB-839 or BPTES. All three inhibitors regulate the enzymatic activity of GAC via a similar allosteric mechanism. 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. In vitro, UPGL00004 inhibits MDA-MB-231 and HS578T, TSE cells with IC50S of 70, 129, and 262 nM, respectively.

In vivo, the authors combine UPGL00004 and Bevacizumab to treat triple-negative breast cancer patient-derived tumor graft model. It completely prevents any detectable increase in tumor size during the course of treatment.

All in all, UPGL00004 is a potent allosteric GAC inhibitor, which strongly inhibits the proliferation of highly aggressive triple-negative breast cancer cell lines.

Reference:

Huang Q, et al. J Biol Chem. 2018 Mar 9;293(10):3535-3545.

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