molecules of the month

The Agios first-in-class oral MAT2A enzyme allosteric inhibitor, AG-270, is a Ph. I clinical candidate for tumors with MTAP gene loss. The inhibitor works on a synthetic lethality principle: the MTAP-loss which drives tumors also makes them particularly sensitive to reduction in S- adenosyl methionine (SAM) levels, and since MAT2A is the primary producer of SAM, inhibition of MAT2A leads to MTAP- tumor killing while healthy tissues are largely unaffected. Remarkably, the program started from a 620 μM fragment hit detected by SPR, and the challenging pyrazolopyrimidone core structure with multiple tautomeric states was carried through to the clinical candidate (despite multiple attempts to replace it). Though MAT2A inhibition has previously been shown to result in a feedback loop resulting in MAT2A upregulation, AG-270 appears to…