| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Targets |
PKI-179 targets mTOR and phosphoinositide-3-kinase (PI3K) alpha. It demonstrates IC50 values of 8 nM for PI3K-α, 24 nM for PI3K-β, 74 nM for PI3K-γ, 77 nM for PI3K-δ, and 0.42 nM for mTOR. The compound also inhibits PI3K α E545K and α H1047R mutants with IC50 values of 14 nM and 11 nM, respectively. It exhibits much reduced or little activity against a panel of 361 other kinases (IC50 >50 μM), cytochrome CYP isoforms, or hERG (IC50 >30 μM).
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| ln Vitro |
With IC50 values of 22 nM and 29 nM for MDA361 and PC3 cells, respectively, PKI-179 suppresses cell growth [1]. PKI-179 is active against CYP2C8 (IC50=3 μM) but inactive against a panel of 361 additional kinases, hERG, and cytochrome P450 (CYP) isoforms at concentrations up to >30 μM [1].
PKI-179 inhibits cell proliferation with IC50 values of 22 nM for MDA361 breast cancer cells and 29 nM for PC3 prostate cancer cells. It effectively suppresses cancer growth in cultures in vitro. The compound 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 (IC50=3 μM). The major metabolite remains biologically potent against kinase targets. |
| ln Vivo |
PKI-179 (5-50 mg/kg; taken orally once daily for 40 days) inhibits tumor growth and is well tolerated in nude mice bearing MDA-361 human breast cancer tumors [1]. PKI-179 (50 mg/kg; orally) exerts favorable inhibitory effects on PI3K signaling in nude mice bearing MDA361 tumor xenografts [1]. PKI-179 has good oral bioavailability (98% in nude mice, 46% in rats, 38% in monkeys, and 61% in dogs) and a long half-life (>60 minutes) [1].
PKI-179 effectively suppresses cancer growth in mice in vivo. In MDA361 tumor-bearing mice, daily oral administration at 50 mg/kg/day resulted in 30% reduction in tumor size on day 42. At 10 mg/kg/day, tumor size was reduced by 40%. The compound induces apoptosis as a result of Akt/mTOR pathway inhibition. It has been shown to inhibit tumor growth in breast cancer, prostate cancer, and colon cancer models and prolongs survival of cancer-bearing mice. |
| Enzyme Assay |
Specific cell-free enzyme/receptor binding assay protocols for PKI-179 involve kinase inhibition assays. PI3K isoform activity is measured using purified enzymes and appropriate substrates, with IC50 values determined for PI3K-α (8 nM), PI3K-β (24 nM), PI3K-γ (74 nM), and PI3K-δ (77 nM). mTOR kinase activity is assessed with an IC50 of 0.42 nM. Selectivity is evaluated against a panel of 361 kinases, CYP isoforms, and hERG.
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| Cell Assay |
In vitro cell-based assays for PKI-179 use MDA361 breast cancer cells and PC3 prostate cancer cells. Cells are treated with PKI-179 at varying concentrations for 72 hours, and cell proliferation is assessed using standard assays such as MTT or CellTiter-Glo to determine IC50 values (22 nM and 29 nM respectively). Apoptosis induction is confirmed through caspase activation assays and Annexin V staining.
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| Animal Protocol |
Animal/Disease Models: Nude mice bearing MDA-361 human breast cancer tumors [1] Doses: 5, 10, 25, 50 mg/kg
Route of Administration: intraperitoneal (ip) injection every 3 days for 4 weeks Experimental Results: Doses exceeding 10 mg /kg, demonstrated significant tumor growth arrest. For all different doses, no significant weight loss was observed in the test animals. In vivo animal studies for PKI-179 use MDA361 tumor-bearing mice. The compound is administered orally at doses of 10 mg/kg/day or 50 mg/kg/day. Tumor size is measured over time, with reductions of 40% (at 10 mg/kg) and 30% (at 50 mg/kg) observed on day 42. The compound induces apoptosis via Akt/mTOR pathway inhibition. Efficacy has been demonstrated in breast, prostate, and colon cancer models. |
| ADME/Pharmacokinetics |
PKI-179 is orally bioavailable in mouse, rat, monkey, and dog with bioavailabilities of 98%, 46%, 38%, and 61%, respectively, at 10 mg/kg. Liver microsome stability data indicate faster metabolism in human (t1/2 = 14 min) and monkey than in mouse and rat (t1/2 >30 min) and dog. The major metabolite remains potent against kinase targets (IC50 = 0.8 nM for mTOR, 4 nM for PI3K-α, and 33 nM for PI3K-γ) and cancer cells (IC50 = 32 nM for MDA361 and 80 nM for PC3mm2). Molecular weight: 488.55 g/mol.
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| Toxicity/Toxicokinetics |
Specific toxicological data for PKI-179 are limited. The compound exhibits much reduced or little activity against hERG (IC50 >30 μM) and a panel of 361 other kinases (IC50 >50 μM). It does show activity for CYP2C8 with an IC50 of 3 μM. A Phase 1 clinical trial (NCT00997360) was initiated but terminated. The compound is classified for research use only.
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| References |
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| Additional Infomation |
See also: Pki-179 (Notes have been moved to).
PKI-179 (CAS 1197160-28-3) is a second-generation, orally bioavailable dual PI3K/mTOR inhibitor developed by Wyeth (now Pfizer). It demonstrates IC50 values of 8 nM for PI3K-α, 24 nM for PI3K-β, 74 nM for PI3K-γ, 77 nM for PI3K-δ, and 0.42 nM for mTOR. The compound has shown efficacy in breast, prostate, and colon cancer models. A Phase 1 clinical trial (NCT00997360) in subjects with advanced malignant solid tumors was initiated in February 2010 but terminated. |
| Molecular Formula |
C25H28N8O3
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|---|---|
| Molecular Weight |
488.54162
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| Exact Mass |
488.228
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| CAS # |
1197160-28-3
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| Related CAS # |
PKI-179 hydrochloride;1463510-35-1
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| PubChem CID |
46947264
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| Appearance |
Off-white to yellow solid powder
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| LogP |
2.406
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
36
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| Complexity |
714
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WXUUCRLKXQMWRY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H28N8O3/c34-25(28-19-7-9-26-10-8-19)27-18-3-1-17(2-4-18)22-29-23(32-11-13-35-14-12-32)31-24(30-22)33-20-5-6-21(33)16-36-15-20/h1-4,7-10,20-21H,5-6,11-16H2,(H2,26,27,28,34)
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| Chemical Name |
1-[4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]phenyl]-3-pyridin-4-ylurea
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| Synonyms |
PK I179; PKI-179; PKI179
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~204.69 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.12 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0469 mL | 10.2346 mL | 20.4692 mL | |
| 5 mM | 0.4094 mL | 2.0469 mL | 4.0938 mL | |
| 10 mM | 0.2047 mL | 1.0235 mL | 2.0469 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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