Deciphering the landscape of allosteric glutaminase 1 inhibitors as anticancer agents

Glutamine is the second most utilised energy source after glucose for cancer cells to support their proliferation and survival. Glutaminase 1 (GLS1) is the rate-limiting enzyme during the glutaminolysis pathway and thus represents a promising therapeutic target for the development of innovative antitumor agents. Two main classes of GLS1 inhibitors, based on their different binding mode, are reported: the substrate active site and the allosteric site inhibitors. Despite the intense efforts made to date, only two GLS1 inhibitors (i.e.,CB-839 and IPN60090) have entered clinical trials. Therefore, this research field remains to be explored to improve the effectiveness of anticancer therapy. Hence, we describe the discovery and development of reversible allosteric GLS1 inhibitors disclosed in the last six years, dividing them based on their structural similarity with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and CB-839. Furthermore, macrocyclic and thiadiazole derivatives, and other structurally different compounds are discussed to present a wider picture of the chemical space under investigation. The study of the binding interactions governing GLS1 inhibition is also analyzed, to help prospectively refine the structural features for greater efficacy. Interestingly, an overview of a new class of irreversible allosteric inhibitors targeting GLS1 Lys320 key residue is provided for the first time. We also summarize the most important biological studies conducted on CB-839 and IPN60090 and their significance for further assessment. The insights garnered from this paper are expected to guide future drug design endeavours toward the identification of novel therapeutics targeting GLS1 to complement and potentially enhance the arsenal of anticancer medications.