Journey of Methionine Adenosyltransferase 2A Inhibitors: From Bench to Advanced Clinical Trials
Abstract
Methionine adenosyltransferase 2A (MAT2A) represents a promising target in precision oncology, especially for cancers with methylthioadenosine phosphorylase (MTAP) deletions. MAT2A inhibition induces synthetic lethality in MTAP-deleted cancers by depleting S -adenosylmethionine (SAM) and enhancing the inherent suppression of protein arginine methyltransferase 5 (PRMT5). Here, we trace the evolution of MAT2A inhibitors from early substrate-competitive molecules to allosteric inhibitors now in clinical evaluation. We discuss the design of next-generation inhibitors with improved potency, selectivity, and pharmacokinetic properties, including central nervous system penetration.
Fields of Study & Subjects
Folate and B Vitamins Research
Peptidase Inhibition and Analysis
Nitrogen and Sulfur Effects on Brassica
Publication details
- Journal / source
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Volume
- 69
- Issue
- 5
- Pages
- 5063–5078
- Publication date
- 25 February 2026
- Language
- EN