AG-270 (C09-1103-060)

AG-270 is an allosteric, noncompetitive, first-in-class, reversible and orally active MAT2A inhibitor, with an IC 50 of 14 nMIn VitroAG-270 demonstrates potent reduction in levels of intracellular SAM , as well as MTAP-–selective antiproliferative activity in the HCT116 MTAP isogenic cell model in vitro. AG-270 exhibits an IC 50 of 20 nM in HCT116 MTAP- cell SAM at 72 h. MAT2A is a key enzyme in the methionine salvage pathway, responsible for generating the universal methyl donor, S-adenosylmethionine (SAM). MCE has not independently confirmed the accuracy of these methods. They are for reference only.In VivoAG-270 shows excellent microsomal, hepatocyte, and in vivo metabolic stability across species (human, mouse, rat, dog, and monkey). AG-270 exhibits T1/2 values of 5.9 h, 4.2 h, 4.8 h and 21.3 h in mouse, rat, monkey and dog, respectively . AG-270 (200 mg/kg, orally, q.d. for 38 days) results in dose-dependent reduction in tumor SAM levels and tumor growth of KP4 MTAP- xenografts and is well tolerated, with mean body weight loss <5% . Combining AG-270 with taxanes and gemcitabine yielded additive-tosynergistic antitumor activity, with the docetaxel combination yielding 50% complete tumor regressions in select models; combination benefits are observed in PDX models derived from esophageal, NSCLC, and pancreatic cancers. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Pancreatic KP4 MTAP - xenograft mouse model . Dosage: 10-200 mg/kg. Administration: Orally, q.d. for 38 days. Result: Led to dose-dependent reductions in tumor SAM levels and tumor growth of KP4 MTAP- xenografts (TGI = 36% (10 mg/kg), 48% (30 mg/kg), 66% (100 mg/kg), 67% (200 mg/kg).IC50& Target:IC50: 14 nM (MAT2A). Specification: 10mM in DMSO Molecular Formula: C30H27N5O2 Molecular Weight: 489.57