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Beschreibung

A cell-permeable triazinyl-phenyl-pyridinylurea compound that acts as a potent inhibitor against mTOR (IC = 0.42 nM) and PI 3-K (IC = 8, 24, 74, 77, 14, and 11 nM against isoform &alpha,, &beta,, &gamma,, &delta,, &alpha, E545K mutant, and &alpha, H1047R mutant, respectively) activities, exhibiting much reduced or little activity against a panel of 361 other kinases (IC >50 microM), Cytochrome CYP isoforms, or hERG. It is reported to be orally available in mouse, rat, monkey, and dog species, and effectively suppress cancer growth both in cultures in vitro (IC = 22 and 29 nM, respectively, against MDA361 and PC3mm2) and in mice in vivo (by 30% of control MDA361 tumor size on day 42, 50 mg/kg/day p.o.) via apoptosis induction as a result of Akt/mTOR pathway inhibition., A cell-permeable triazinyl-phenyl-pyridinylurea compound that acts as a potent inhibitor against mTOR and PI 3-K activities (IC₅₀ = 0.42 nM against mTOR, IC₅₀ = 8, 24, 74, 77, 14, and 11 nM against PI 3-K isoform &alpha,, &beta,, &gamma,, &delta,, &alpha, E545K mutant, and &alpha, H1047R mutant, respectively), exhibiting much reduced potency against Cytochrome CYP 2C8 (IC₅₀ = 3 microM) and little or no activity toward 7 other Cytochrome CYP isoforms, hERG (IC₅₀ >30 microM) and a panel of 361 other kinases (IC₅₀ >50 microM). It is reported to be orally available in mouse, rat, monkey, and dog (bioavailability = 98%, 46%, 38%, and 61%, respectively, 10 mg/kg), and effectively suppress cancer growth both in cultures in vitro (IC₅₀ = 22 and 29 nM, respectively, against MDA361 and PC3mm2) and in mice in vivo (40% and 30% of control MDA361 tumor size on day 42, respectively, via daily p.o. dosage of 10 mg/kg and 50 mg/kg) via apoptosis induction as a result of Akt/mTOR pathway inhibition. Although liver microsome stability data indicate a much faster compound metabolism in human (t_1/>> = 14 min) and monkey than in mouse, rat (t_1/>> >30 min), and dog, the major metabolite remains biologically potent against kinase targets (IC₅₀ =0.8, 4, and 33 nM against mTOR, PI 3-K&alpha,, and PI 3-&gamma,, respectively) and cancer cell proliferation (IC₅₀ = 32 and 80 nM, respectively, against MDA361 and PC3mm2)., The PI 3-K/mTOR Inhibitor III, PKI-179, also referenced under CAS 1197160-28-3, controls the biological activity of PI 3-K/mTOR. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.