AG-270

AG-270 is a well-characterised tool compound for the study of allosteric MAT2A inhibition both in cells and in vivo mouse models at the recommended concentration and dose ranges. However, AG-270 has low aqueous solubility (< 1.0 uM at pH 7.4) and required a spray-dried dispersion formulation for oral pharmacokinetic studies in higher species. Oral dosing in mouse models bearing human tumour xenografts utilised a bespoke formulation (6.7 % w/w HPMCAS-MF, 1% w/w PVP K30, 2% w/w TPGS, 0.1% Simethicone) – see J. Med Chem. 2021, 64, 4430-4449 Supplementary Information. Thus, care is required in the formulation of AG-270 to ensure adequate exposure in both cell-based and especially in vivo studies.

The compound is poorly soluble thus special care must be taken when preparing formulations for in vivo work. Specifically, the compound must be prepared as a spray-dried dispersion.

AG-270 was developed from a relatively weak binder and abundant SAR data and co-crystal structures with its intended target MAT2A, demonstrate the inhibition mechanism. Cellular and in vivo effects make sense with the expected phenotypes and it appears there are no obvious off-target effects in cellular assays. Negative control compounds for AG-270 exist. Proteome-wide selectivity has not yet been demonstrated by using MAT2A resistance alleles, however, this is a minor concern since collectively all the available data suggests that AG-270 is a potent and selective inhibitor of MAT2A.