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

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.