AG-270

• CAT Number: I044594
• CAS Number: 2201056-66-6
• Molecular Formula: C30H27N5O2
• Molecular Weight: 489.57
• Purity: ≥95%
• Synonyms: 3-(cyclohexen-1-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2-ylamino)-1H-pyrazolo[1,5-a]pyrimidin-7-one
• InChI: InChI=1S/C30H27N5O2/c1-37-23-17-15-21(16-18-23)26-28(32-24-14-8-9-19-31-24)33-29-25(20-10-4-2-5-11-20)27(34-35(29)30(26)36)22-12-6-3-7-13-22/h3,6-10,12-19,34H,2,4-5,11H2,1H3,(H,31,32)
• InChIKey: LSOYYWKBUKXUHQ-UHFFFAOYSA-N
• SMILES: COC1=CC=C(C=C1)C2=C(N=C3C(=C(NN3C2=O)C4=CC=CC=C4)C5=CCCCC5)NC6=CC=CC=N6

AG-270 is an allosteric, noncompetitive, first-in-class, reversible and orally active MAT2A inhibitor, with an IC50 of 14 nM[1].
AG-270 demonstrates potent reduction in levels of intracellular SAM, as well as MTAP-null–selective antiproliferative activity in the HCT116 MTAP isogenic cell model in vitro[1].
AG-270 exhibits an IC50 of 20 nM in HCT116 MTAP-null cell SAM at 72 h[1].
MAT2A is a key enzyme in the methionine salvage pathway, responsible for generating the universal methyl donor, S-adenosylmethionine (SAM)[2].
AG-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[1].
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-null xenografts and is well tolerated, with mean body weight loss <5%[1]. 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[2].

Reference

[1]. Zenon Konteatis, et al. Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion. J Med Chem. 2021 Apr 8.
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[2]. Marc L Hyer, et al. The MAT2A inhibitor AG-270 combines with both taxanes and gemcitabine to yield enhanced antitumor activity in patient-derived xenograft models.