AT13148

AT13148 is an orally active and ATP-competitive, multi-AGC kinase inhibitor with IC₅₀s of 38 nM/402 nM/50 nM, 8 nM, 3 nM, and 6 nM/4 nM for Akt1/2/3, p70S6K, PKA, and ROCKI/II, respectively. IC50 & Target:IC50: 38 nM (Akt1), 402 nM (Akt2), 50 nM (Akt3), 8 nM (p70S6K), 3 nM (PKA), 6 nM (ROCKI), 4 nM (ROCKII) In Vitro: AT13148 inhibits a panel of kinases at 10 μM, and the IC₅₀ values for p70S6K, PKA, ROCKI, and ROCKII are all less than 10 nM and those for AKT1, 2, and 3 are 38, 402, and 50 nM, respectively. For the related AGC kinases RSK1 and SGK3, the IC₅₀ values are 85 and 63 nM, respectively. In contrast, IC₅₀ values for the non-AGC kinases CHK2 and Aurora B are both greater than 800 nM. AT13148 potently inhibits proliferation with GI₅₀ values of 1.5 to 3.8 μM across a selected panel of cancer cell lines^[1]. AT13148 treatment in gastric cancer cells dramatically suppresses activation of multiple AGC kinases, including Akt (at p-Thr-308), p70S6 kinase (p70S6K), glycogen synthase kinase 3β (GSK-3β) and p90 ribosomal S6 kinase (RSK)^[2]. In Vivo: Oral drug administration of 5 mg/kg of AT13148 results in complete bioavailability. Clear inhibition of phosphorylation of the AKT substrates GSK3β, tuberin, and the p70S6K target S6RP are also observed in PTEN-deficient MES-SA human uterine tumor xenografts after treatment with 40 and 50 mg/kg p.o. of AT13148^[1]. Oral gavage of AT13148 at well-tolerated doses significantly inhibits HGC27 xenograft tumor growth in nude mice. AGC activity is also dramatically decreased in AT13148-administrated HGC27 tumors^[2].