Glutaminase (GLS), which is responsible for the conversion of glutamine to glutamate, plays a
vital role in up-regulating cell metabolism for tumor cell growth and is considered to be a valuable therapeutic
target for cancer treatment. Based on this important function of glutaminase in cancer, several
GLS inhibitors have been developed in both academia and industry. Most importantly, Calithera Biosciences
Inc. is actively developing the glutaminase inhibitor CB-839 for the treatment of various cancers,
and it is currently being evaluated in phase 1 and 2 clinical trials. In this review, recent efforts to
develop small molecule glutaminase inhibitors that target glutamine metabolism in both preclinical and
clinical studies are discussed. In particular, more emphasis is placed on CB-839 because it is the only
small molecule GLS inhibitor being studied in a clinical setting. The inhibition mechanism is also discussed
based on X-ray structure studies of thiadiazole derivatives present in glutaminase inhibitor
BPTES. Finally, recent medicinal chemistry efforts to develop a new class of GLS inhibitors are described
in the hopes of providing useful information for the next generation of GLS inhibitors.
Keywords: Glutaminase, glutaminase inhibitors, cancer target, BPTES, CB-839, allosteric inhibitors.
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