| Identification | Back Directory | [Name]
PKI-179 (hydrochloride) | [CAS]
1463510-35-1 | [Synonyms]
PKI-179 (hydrochloride)
PKI179 hydrochloride,PKI 179 hydrochloride
N-[4-[4-(4-morpholinyl)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]phenyl]-N'-4-pyridinyl-urea,monohydrochloride | [Molecular Formula]
C25H29ClN8O3 | [MDL Number]
MFCD34469322 | [MOL File]
1463510-35-1.mol | [Molecular Weight]
525.01 |
| Chemical Properties | Back Directory | [storage temp. ]
Store at -20°C | [solubility ]
DMF: 2 mg/ml; DMSO: 2.5 mg/ml; DMSO:PBS(pH 7.2) (1:3): 0.25 mg/ml; Ethanol: slightly soluble | [form ]
A crystalline solid | [color ]
White to off-white |
| Hazard Information | Back Directory | [Description]
PKI-179 is an orally bioavailable dual inhibitor of PI3K and mammalian target of rapamycin (mTOR). In an in vitro enzymatic assay, it potently inhibits PI3K (IC50s = 8, 24, 17, and 74 nM for isoforms α, β, δ, and γ, respectively), two common PI3Kα mutants, E545K and H1047R (IC50s = 14 and 11 nM, respectively), and mTOR (IC50 = 0.42 nM). PKI-179 is selective for PI3K and mTOR over a panel of 361 other kinases at IC50 values up to 50 μM, hERG (IC50 > 30 μM), and cytochrome P450 (CYP) isoforms (IC50s > 30 μM), but does have activity for CYP2C8 (IC50 = 3 μM). It inhibits proliferation through the Akt/mTOR signaling pathway in MDA-361 breast and PC3MM2 prostate cancer cell lines in vitro (IC50s = 22 and 29 nM, respectively) and inhibits tumor growth in an MDA-361 mouse xenograft model when used at a dose of 50 mg/kg. | [Uses]
PKI-179 hydrochloride is a potent and orally active dual PI3K/mTOR inhibitor, with IC50s 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 IC50s of 14 nM and 11 nM, respectively. PKI-179 hydrochloride shows anti-tumor activity in vivo[1][2]. | [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[1].
PKI-179 (50 mg/kg; p.o.) results in good inhibition of PI3K signaling in nude mice bearing MDA361 tumor xenografts[1].
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) [1]. | Animal Model: | Nude mice bearing MDA-361 human breast cancer tumors[1] | | 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.
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| [IC 50]
mTOR: 0.42 nM (IC50); PI3Kα: 8 nM (IC50); PI3Kβ: 24 nM (IC50); PI3Kγ: 74 nM (IC50); PI3Kδ: 77 nM (IC50); E545K: 14 nM (IC50); H1047R: 77 nM (IC50) | [storage]
Store at -20°C | [References]
[1] Venkatesan AM, et, al. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. DOI:10.1016/j.bmcl.2010.07.104
[2] Rehan M. A structural insight into the inhibitory mechanism of an orally active PI3K/mTOR dual inhibitor, PKI-179 using computational approaches. J Mol Graph Model. 2015 Nov;62:226-234. DOI:10.1016/j.jmgm.2015.10.005 |
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