A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight.

Autor:	Cuthbertson CR; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Arabzada Z; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Bankhead A 3rd; Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, United States.; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States., Kyani A; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Neamati N; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2021 Mar 01; Vol. 4 (2), pp. 624-646. Date of Electronic Publication: 2021 Mar 01 (Print Publication: 2021).
DOI:	10.1021/acsptsci.0c00223
Abstrakt:	Metabolic reprogramming is a key hallmark of cancer and shifts cellular metabolism to meet the demands of biomass production necessary for abnormal cell reproduction. One-carbon metabolism (1CM) contributes to many biosynthetic pathways that fuel growth and is comprised of a complex network of enzymes. Methotrexate and 5-fluorouracil were pioneering drugs in this field and are still widely used today as anticancer agents as well as for other diseases such as arthritis. Besides dihydrofolate reductase and thymidylate synthase, two other enzymes of the folate cycle arm of 1CM have not been targeted clinically: serine hydroxymethyltransferase (SHMT) and methylenetetrahydrofolate dehydrogenase (MTHFD). An increasing body of literature suggests that the mitochondrial isoforms of these enzymes (SHMT2 and MTHFD2) are clinically relevant in the context of cancer. In this review, we focused on the 1CM pathway as a target for cancer therapy and, in particular, SHMT2 and MTHFD2. The function, regulation, and clinical relevance of SHMT2 and MTHFD2 are all discussed. We expand on previous clinical studies and evaluate the prognostic significance of these critical enzymes by performing a pan-cancer analysis of patient data from the The Cancer Genome Atlas and a transcriptional coexpression network enrichment analysis. We also provide an overview of preclinical and clinical inhibitors targeting the folate pathway, the methionine cycle, and folate-dependent purine biosynthesis enzymes. Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.)
Databáze:	MEDLINE
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