PCYT1A inhibitor

PCYT1A inhibitors are a class of therapeutic agents designed to target phosphate cytidylyltransferase 1, choline-alpha (PCYT1A), the rate-limiting enzyme in the Kennedy pathway for phosphatidylcholine biosynthesis. Research presented at the EHA 2026 Annual Congress identifies PCYT1A as a robust synthetic lethal vulnerability in monocytic acute myeloid leukemia (AML), particularly in subtypes driven by MLL (KMT2A) rearrangements. This vulnerability arises from the lineage-specific absence of the paralog PCYT1B in monocytic cells, creating a dependency on PCYT1A for survival. Mechanistically, inhibition or depletion of PCYT1A triggers a compensatory upregulation of phosphatidylethanolamine N-methyltransferase (PEMT), which hyperactivates the methionine cycle and one-carbon metabolism. This metabolic rewiring leads to a toxic accumulation of S-adenosylmethionine (SAM), resulting in growth suppression and differentiation of leukemic cells. The PCYT1A-PEMT axis represents a novel metabolic crosstalk and a promising therapeutic strategy for high-risk, lineage-defined AML.

Other names

PCYT1A inhibitorPCYT-1A inhibitorPCYT 1A inhibitorCCT-alpha inhibitorPhosphate cytidylyltransferase 1 choline-alpha inhibitor