AG-270 is a reversible, allosteric, noncompetitive MAT2A inhibitor, representing a first-in-class orally active compound, with an IC50 of 14 nM [1].
体内研究
AG-270 demonstrates robust metabolic stability across multiple species (human, mouse, rat, dog, and monkey) in microsomal, hepatocyte, andin vivo settings. It exhibits half-life values of 5.9 h, 4.2 h, 4.8 h, and 21.3 h in mouse, rat, monkey, and dog, respectively [1].
Following oral administration at 200 mg/kg once daily for 38 days, AG-270 induces dose-dependent reductions in tumor SAM levels and tumor growth in KP4 MTAP-null xenografts. It is well tolerated, with mean body weight loss less than 5% [1].
Combining AG-270 with taxanes and gemcitabine demonstrates additive-to-synergistic antitumor effects, with the docetaxel combination yielding 50% complete tumor regressions in select models. These combination benefits are observed in patient-derived xenograft (PDX) models derived from esophageal, non-small cell lung cancer (NSCLC), and pancreatic cancers [2].
体外研究
AG-270 demonstrates significant reduction in intracellular SAM levels and exhibits MTAP-null–selective antiproliferative effects in the HCT116 MTAP isogenic cell model in vitro[1].
In HCT116 MTAP-null cells, AG-270 displays an IC50 of 20 nM for SAM at 72 h [1].
MAT2A plays a pivotal role in the methionine salvage pathway, facilitating the production of S-adenosylmethionine (SAM), the universal methyl donor [2].
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