PI 3-K/mTOR Inhibitor III, PKI-179

A cell-permeable triazinyl-phenyl-pyridinylurea compound that acts as a potent inhibitor against mTOR (IC₅₀ = 0.42 nM) and PI 3-K (IC₅₀ = 8, 24, 74, 77, 14, and 11 nM against isoform α, β, γ, δ, α E545K mutant, and α H1047R mutant, respectively) activities, exhibiting much reduced or little activity against a panel of 361 other kinases (IC₅₀ >50 µM), 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 (IC₅₀ = 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 α, β, γ, δ, α E545K mutant, and α H1047R mutant, respectively), exhibiting much reduced potency against Cytochrome CYP 2C8 (IC₅₀ = 3 µM) and little or no activity toward 7 other Cytochrome CYP isoforms, hERG (IC₅₀ >30 µM) and a panel of 361 other kinases (IC₅₀ >50 µM). 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-Kα, and PI 3-γ, 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.

Packaged under inert gas

Toxicity: Regulatory Review (Z)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Venkatesan, A.M., et al. 2010. Bioorg. Med. Chem. Lett.20, 5869.
Chen, Z., et al. 2010. J. Org. Chem.75, 1643.

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