MTHFD1 and MTHFD2 (dual)

Class

Dual MTHFD1/MTHFD2 inhibitor

Pathway

One-carbon (folate) metabolism; induces folate trapping and disrupts DNA damage response/repair

MTHFD1 and MTHFD2 are enzymes in one-carbon (folate) metabolism, the biochemical network that shuttles single-carbon units derived from folate cofactors into building blocks for DNA synthesis and into methylation reactions throughout the cell. MTHFD1 operates in the cytoplasm and is present in most dividing cells, while MTHFD2 resides in mitochondria and is characteristically overexpressed in many cancers while being largely absent from normal adult tissue. Inhibiting only one of these enzymes often fails because the other compartment can partially compensate, sustaining enough one-carbon flux to keep synthesizing purines and thymidylate (a DNA building block). A dual inhibitor blocks both the mitochondrial and cytoplasmic arms simultaneously, producing a more complete disruption of one-carbon supply, a phenomenon described as folate trapping, in which folate cofactors accumulate in a form the cell cannot use productively. The resulting shortage of DNA precursors impairs replication and interferes with the cellular machinery that detects and repairs DNA damage, a vulnerability that is particularly pronounced in rapidly dividing cancer cells with high biosynthetic demand. This mechanism is of interest broadly in oncology, especially in tumors that show elevated reliance on mitochondrial one-carbon metabolism, and it draws conceptually on the older tradition of antifolate chemotherapy while aiming for a more selective and complete blockade of the pathway.