Table 1.

Drugs Targeting Glutamine, Serine, and 1-C Metabolism.

Classification	Mechanism of Action	Examples	Pre-Clinial/Clinial Usage
Glutamine Metabolism
Asparaginase	Depletes glutamine in the plasma by converting glutamine/asparagine to glutamate/aspartate and ammonia	E.Coli [Asparaginase (short acting), pegasparagase (long acting) Erwinia Chrysantemi [Erwinaze or crisantasapase (short acting)]; PegCrisantaspase [(PegC), long acting, under clinical and pre-clinical investigation for ALL and AML]	ALL [40] Pre-clinical studies in AML [11,30,52,54]
Glutaminase Inhibitor	Inhibits the hydrolase enzyme that converts glutamine to glutamate	BPTES CB-839	Pre-clinical studies in Breast Cancer [41] and AML [42]
Glutamine Transporter Inhibitor	Inhibits transport of glutamine in the cell (PM and mitochondria)	V-9302	Pre-clinical studies in CRC [43]
Glutamine Antagonist/Analog	Direct blockage of glutamine metabolism	JHU083 L-DON	Pre-clinical studies in Medulla Blastoma [45]
Serine Biosynthesis
Phosphoglycerate dehydrogenase (PHGDH) Inhibitor	Inhibits the rate limiting step of serine biosynthesis (PHGDH)	CBR-5884 NCT-503	Pre-clinical studies in Breast Cancer [6,44] and AML [10]
Serine hydroxymethyltransferase (SHMT) Inhibitor	Inhibits the enzyme (SHMT) that catalyzes the conversion of serine to glycine and initiates the folate cycle	SHIN2	Pre-clinical studies in T-ALL [16]
1-C Metabolism
Anti-Folates	Antagonize the actions of folic acid and inhibit key enzymes in the folate cycle including: Thymidylate synthase (TS), Dihydrofolate reductase (DHFR), Glycinamide ribonucleotide formyltransferase (GARFT)	Methotrexate Pemetrexed	ALL, Breast Cancer, HNSCC, Non-Hodgkin Lymphoma and Osteosarcoma [21,22] Malignant pleural mesothelioma Non-squamous NSCL cancer
Anti-Metabolites	Analogues of a normal metabolites that inhibit key enzymes in the folate cycle including: Thymidylate synthase (TS)	5-Fluorouracil Capecitabine	Colorectal Cancer, Breast Cancer, Gastrointestinal Cancers and HNSCC [22]