BMS-986456

BMS-986456 is an orally bioavailable small molecule inhibitor of methionine adenosyltransferase 2A (MAT2A), currently under development by Bristol Myers Squibb for the treatment of MTAP-deleted advanced solid tumors, including pancreatic ductal adenocarcinoma. MAT2A is the primary enzyme responsible for the synthesis of S-adenosylmethionine (SAM) from methionine and ATP. In tumors harboring a deletion of the methylthioadenosine phosphorylase (MTAP) gene, the metabolite methylthioadenosine (MTA) accumulates and acts as a partial endogenous inhibitor of the protein arginine methyltransferase PRMT5. By further depleting SAM levels through MAT2A inhibition, BMS-986456 induces a state of synthetic lethality, leading to profound inhibition of PRMT5 activity, disruption of RNA splicing, and subsequent tumor cell death.

Other names

2-[4-[4-(aminomethyl)-1-oxo-2h-phthalazin-6-yl]-2-methylpyrazol-3-yl]-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile2-(4-(4-(aminomethyl)-1-oxophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile