Completed the single agent dose-escalation portion of the ongoing Phase 1 study of AG-270 in methylthioadenosine
phosphorylase (MTAP)-deleted tumors.
phosphorylase (MTAP) is an enzyme involved in purine metabolism that plays a role in salvage of adenosine and methionine.
phosphorylase (MTAP, Table 2, spot 6 and Table 3, spot 2) catalyzes the reversible phosphorolytic cleavage of methylthioadenosine
, a by-product of the polyamine biosynthesis, producing methylthioribose-1-phosphate (MTRP) and adenine.
Gilchrist et al., "Human genetic and metabolite variation reveals that methylthioadenosine
is a prognostic biomarker and an inflammatory regulator in sepsis," Science Advances, vol.
) is generated as a byproduct.
The 9p21 gene is associated with coronary heart disease and Ml, but also with cancer through the MTAP (methylthioadenosine
Treatment of endothelial cells with a H3K4 methylation inhibitor methylthioadenosine
resulted in decreased eNOS expression, while treating nonexpressing cells with histone deacetylase inhibitor, trichostatin-A, increased eNOS expression .
BPDCN, blastic plasmacytoid dendritic cell neoplasm; CDKN, cyclin-dependent kinase inhibitor; MTAP, methylthioadenosine
phosphorylase; TRAF2, tumor necrosis factor receptor-associated factor 2; CARD9, caspase recruitment domain; RB1, retinoblastoma tumor suppressor gene; CYP1A1, cytochrome P450 family 1 subfamily a polypeptide 1; PRKCSH, protein kinase C substrate 80K-H; PTPN23, protein-tyrosine-phosphatase-n23; MCC, mutated in colorectal cancer; APC, adenomatous polyposis coli tumor suppressor gene; PARK2, Parkinson protein 2; MAD1L1, mitotic arrest deficient-like 1; TP53, tumor protein 53.
S-adenosylmethionine and methylthioadenosine
are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells.
Its by-product methylthioadenosine
(MTA) is a natural analgesic and anti-inflammatory.
This locus also contains the MTAP (methylthioadenosine
phosphorylase) gene (Fig.
(3) This region contains the coding sequence for two cyclin-dependent kinase inhibitors, CDKN2A and CDKN2B, which play an important role in the regulation of the cell cycle and have been implicated in the pathogenesis of atherosclerosis, as well as for MTAP, a methylthioadenosine
phosphorylase enzyme important in polyamine metabolism and the salvage of adenine and methionine.