Glutaminase is an enzyme that catalyzes the production of glutamate from the amino acid glutamine, which then feeds into the TCA cycle. This enzyme was initially targeted with the small-molecule inhibitor 6-diazo-5-oxy-l-norleucine (DON). However, a small-molecule compound has been found to selectively inhibit glutaminase; this compound, CB-839, has been shown to exhibit antiproliferative activity against TNBC cell lines and in xenograft murine models, and has successfully moved through phase I clinical trials for both TNBC and renal cell carcinoma. Of note, this small-molecule agent does not act on the glutaminase isoform found in the liver, which is the main isoform believed to be responsible for circulating glutamate, allowing for a better toxicity profile.
