PKI-179 hydrochloride

PKI-179 hydrochloride is a potent and orally active dual PI3K/mTOR inhibitor, with IC 50 s of 8 nM, 24 nM, 74 nM, 77 nM, and 0.42 nM for PI3K-α , PI3K-β , PI3K-γ , PI3K-δ and mTOR , respectively. PKI-179 hydrochloride also exhibits activity over E545K and H1047R , with IC 50 s of 14 nM and 11 nM, respectively. PKI-179 hydrochloride shows anti-tumor activity in vivo In Vitro PKI-179 inhibits the cell proliferation, with IC 50 s of 22 nM and 29 nM for MDA361 and PC3 cells, respectively. PKI-179 shows inhibitory activity against a panel of 361 other kinases, hERG and cytochrome P450 (CYP) isoforms at concentrations up to >30 μM, but does have activity for CYP2C8 (IC 50 =3 μM). MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo PKI-179 (5-50 mg/kg; p.o. once daily for 40 days) inhibits the tumor growth and is well tolerated in nude mice bearing MDA-361 human breast cancer tumors . PKI-179 (50 mg/kg; p.o.) results in good inhibition of PI3K signaling in nude mice bearing MDA361 tumor xenografts . PKI-179 exhibits good oral bioavailability (98% in nude mouse, 46% in rat, 38% in monkey, and 61% in dog) and a high half-life (>60 min) . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Nude mice bearing MDA-361 human breast cancer tumors Dosage: 5, 10, 25, 50 mg/kg Administration: I.p. every 3 days for 4 weeks Result: Exhibited pronounced tumor growth arrest when dosed above 10 mg/kg. No significant weight loss of tested animals was observed for all different dosages. Form:Solid IC50& Target:mTOR 0.42 nM (IC 50 ) PI3Kα 8 nM (IC 50 ) PI3Kβ 24 nM (IC 50 ) PI3Kγ 74 nM (IC 50 ) PI3Kδ 77 nM (IC 50 ) E545K 14 nM (IC 50 ) H1047R 77 nM (IC 50 )

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