Table 2.

Small molecule inhibitors targeting glutaminolysis pathway.

Small Molecule Inhibitors Targeting Glutaminolysis Pathway
Small Molecule Inhibitors	Chemical Structure	Inhibition Type	Enzyme Target	Inhibitory Activity	Reference
6-diazo-5-oxo-l-norleucine (DON)		Irreversible inhibition	Nonselective. Glutamine utilizing enzymes, including glutamine amidotransferases	Inhibits the enzymes by covalently modifying the cysteine residues in the glutamine active sites irreversibly.	PubChem CID: 9087 URL: https://pubchem.ncbi.nlm.nih.gov/compound/9087#section=2D-Structure [38,40,90]
Acivicin		Irreversible inhibition	Nonselective. Glutamine utilizing enzymes, including glutamine amidotransferases, γ-glutamyltranspeptidase (GGT)	Inhibits the enzymes by forming an imine–thioether adduct at the cysteine residue of the active site as a result of nucleophilic substitution of the chlorine atom. Inhibits GGT by covalently modifying the Thr391 residue at the active site.	PubChem CID: 294641 URL: https://pubchem.ncbi.nlm.nih.gov/compound/294641#section=2D-Structure [40,91,92]
Azaserine		Irreversible inhibition	Nonselective. Glutamine utilizing enzymes, including glutamine amidotransferases, γ-glutamyltranspeptidase (GGT)	Inhibits GGT by covalently modifying the Thr391 residue at the active site.	PubChem CID: 460129 URL: https://pubchem.ncbi.nlm.nih.gov/compound/460129#section=2D-Structure [40,92]
l-γ-Glutamyl-p-nitroanilide (GPNA)		Competitive inhibition	Glutamine transporter SLC1A5, sodium-dependent and independent amino acid transporters	Proposed model: Inhibits SLC1A5 by binding to the binding site with high affinity (the ligand part binds to the lipophilic pocket of SLC1A5 and forms a hydrogen bond).	PubChem CID: 81732 URL: https://pubchem.ncbi.nlm.nih.gov/compound/81732#section=2D-Structure [47,48]
V-9302		Competitive inhibition	Glutamine transporter SLC1A5	In silicon model: V-9302 docks into the orthosteric binding site situated at the transmembrane region of SLC1A5.	PubChem CID: 127035871 URL: https://pubchem.ncbi.nlm.nih.gov/compound/127035871#section=2D-Structure [49]
Compound 968		Allosteric inhibition	Glutaminase (GLS): kidney-type glutaminase: kidney glutaminase (KGA) and glutaminase C (GAC), and liver-type glutaminase (GLS2)	Inhibits glutaminases by binding to GAC monomers and preventing the formation of activated GAC tetramers.	PubChem CID: 3099980 URL: https://pubchem.ncbi.nlm.nih.gov/compound/3099980#section=2D-Structure [50–52]
bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES)		Allosteric inhibition	Selectively inhibits kidney-type glutaminase (GLS): kidney glutaminase (KGA) and glutaminase C (GAC)	Inhibits KGA and GAC by trapping their tetramers in a conformation that is nonfunctioning.	PubChem CID: 3372016 URL: https://pubchem.ncbi.nlm.nih.gov/compound/3372016#section=2D-Structure [93–95]
CB-839 (Telaglenastat)		Allosteric inhibition	Selectively inhibits kidney-type glutaminase (GLS): kidney glutaminase (KGA) and glutaminase C (GAC)	Inhibits KGA and GAC by forming hydrogen bonds with cKGA (catalytic domain Ile221-Leu533 of KGA) tetramer.	PubChem CID: 71577426 URL: https://pubchem.ncbi.nlm.nih.gov/compound/71577426#section=2D-Structure [58,59]