Isofagomine Inhibits Multiple TcdB Variants and Protects Mice from -Induced Mortality.

causes life-threatening diarrhea and is one of the leading causes of nosocomial infections. During infection, releases two gut-damaging toxins, TcdA and TcdB, which are the primary determinants of disease pathogenesis and are important therapeutic targets. Once in the cytosol of mammalian cells, TcdA and TcdB use UDP-glucose to glucosylate host Rho GTPases, which leads to cytoskeletal changes that result in a loss of intestinal integrity.

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition.

Homozygous 5'-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human cancers. Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a) induces a synthetic lethal phenotype involving protein arginine methyltransferase 5 (PRMT5) inhibition. MAT2a inhibitors are now in clinical trials for genotypic MTAP cancers, however the MTAP genotype represents fewer than 2% of human colorectal cancers (CRCs), limiting the utility of MAT2a inhibitors in these and other MTAP cancers.

Isofagomine inhibits multiple TcdB variants and protects mice from induced mortality.

causes life-threatening diarrhea and is the leading cause of healthcare associated bacterial infections in the United States. During infection, releases the gut-damaging toxins, TcdA and TcdB, the primary determinants of disease pathogenesis and are therefore therapeutic targets. TcdA and TcdB contain a glycosyltransferase domain that uses UDP-glucose to glycosylate host Rho GTPases, causing cytoskeletal changes that result in a loss of intestinal integrity.