Definition

A broad acting glutamine antagonist, with potential immunomodulatory and antineoplastic activities. Upon administration, DON (6-Diazo-5-oxo-L-norleucine), the active moiety of sirpiglenastat, irreversibly inhibits multiple enzymes involved in glutamine metabolism. Blocking glutamine metabolism inhibits proliferation in rapidly growing tumor cells and leads to an induction of cell death. Unlike normal healthy cells, glutamine-dependent tumors rely heavily on the intracellular conversion of exogenous glutamine into glutamate and glutamate metabolites to both provide energy and generate building blocks for the production of macromolecules, which are needed for cellular growth and survival. In addition, blocking glutamine metabolism leads to the accumulation of glutamine in tumor cells and increases glutamine concentration in the tumor microenvironment (TME) upon tumor cell death. As glutamine is essential for T-cell generation, DON may also enhance T-cell proliferation and activation in the TME, which may lead to further killing of tumor cells. The conversion of sirpiglenastat to the active moiety DON occurs primarily in tumor cells, allowing glutamine metabolism in healthy cells which may lessen adverse effects.