AI Article Synopsis

  • The study focuses on the enzyme MAT2A, which is linked to synthetic lethality in cancers that lack methylthioadenosine phosphorylase, found in about 15% of cancer cases.
  • A new MAT2A inhibitor named SCR-7952 shows strong anti-tumor effects in lab tests and animal studies without raising bilirubin levels.
  • SCR-7952 works well in combination with specific types of PRMT5 inhibitors, enhancing their effectiveness by disrupting PRMT5 function and affecting splicing of the FANCA gene, suggesting its potential as a treatment for -deleted cancers.

Article Abstract

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was found to elicit synthetic lethality in methylthioadenosine phosphorylase ()-deleted cancers, which occur in about 15% of all cancers. Here, we described a novel MAT2A inhibitor, SCR-7952 with potent and selective antitumor effects on -deleted cancers in both in vitro and in vivo. The cryo-EM data indicated the high binding affinity and the allosteric binding site of SCR-7952 on MAT2A. Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. A systematic evaluation of combination between SCR-7952 and different types of protein arginine methyltransferase 5 (PRMT5) inhibitors indicated remarkable synergistic interactions between SCR-7952 and the -adenosylmethionine-competitive or the methylthioadenosine-cooperative PRMT5 inhibitors, but not substrate-competitive ones. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of -deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413503PMC
http://dx.doi.org/10.1002/mco2.705DOI Listing

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