1144068-46-1
1144068-46-1 structure
- Name: WYE-125132(WYE-132)
- Chemical Name: 1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]-3-methylurea
- CAS Number: 1144068-46-1
- Molecular Formula: C27H33N7O4
- Molecular Weight: 519.595
- Catalog: Biochemical Inhibitor PI3K/Akt/mTOR inhibitor (PI3K/Akt/mTOR) mTOR inhibitor
- Create Date: 2018-12-29 16:06:46
- Modify Date: 2024-01-02 19:14:31
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WYE-125132 (WYE-132) is a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC50: 0.19±0.07 nM; >5,000-fold selective versus PI3Ks). WYE-125132 inhibits mTORC1 and mTORC2.
| Name | 1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]-3-methylurea |
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| Synonyms |
cc-15
1-{4-[1-(1,4-Dioxaspiro[4.5]dec-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-methylurea WYE132 1-(4-{1-(1,4-Dioxaspiro[4.5]dec-8-yl)-4-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)-3-methylurea Urea, N-[4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]-N'-methyl- Urea, N-[4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]-N'-methyl- WYE-125132 WYE-132 |
| Description | WYE-125132 (WYE-132) is a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC50: 0.19±0.07 nM; >5,000-fold selective versus PI3Ks). WYE-125132 inhibits mTORC1 and mTORC2. |
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| Related Catalog | |
| Target |
mTOR:0.19 nM (IC50) mTORC1 mTORC2 PI3Kα:1.179 μM (IC50) PI3Kδ:2.38 μM (IC50) hSMG1:1.25 μM (IC50) |
| In Vitro | WYE-125132 (WYE-132) potently inhibits recombinant mTOR via an ATP-competitive mechanism. WYE-125132 is a potent antiproliferative agent against a panel of cancer cell lines with IC50 values generally in the nanomolar range. In the typical 3-day dose-response studies, WYE-125132 exhibits a more profound antiproliferative activity than CCI-779 in MDA361 and other cells, as shown by the sharper inhibition at doses up to 10 μM. Fluorescence-activated cell sorting (FACS) analysis of inhibitor-treated (1 μM, 24 hours) MDA468, PC3MM2, U87MG, A549, and HCT116 cells indicates that WYE-125132 elicits a more profound increase in G1-phase and a reduction in S-phase cells than CCI-779. The WYE-125132–induced cell death is evident at 10 and 30 nM (6.2% and 13%, respectively) and is dose dependent, reaching 47% at 1 μM and 59% at 3 μM[1]. |
| In Vivo | A single i.v. administration of 50 mg/kg WYE-125132 (WYE-132) into tumor-bearing mice leads to suppression of P-S6K(T389) and P-AKT(S473) for at least 8 hours in PC3MM2, MDA361, HCT116, and HT29 tumors, whereas the steady-state level of P-AKT(T308) is not significantly reduced, indicating that the antitumor efficacy of WYE-125132 under such dosing regimens reflects the suppression of mTOR rather than PI3K. Oral administration of WYE-125132 causes dose-dependent tumor growth delay in the PI3K/mTOR- and HER2-hyperactive MDA361 tumors with significant antitumor activity at 5 mg/kg, which correlates with a suppression P-S6 and P-AKT(S473) but not P-AKT(T308). An optimal dose of 50 mg/kg WYE-125132 induces a substantial regression of large MDA361 tumors. WYE-125132 also causes a potent and substantial tumor growth delay in the PTEN-null U87MG glioma[1]. |
| Kinase Assay | mTOR enzyme assays via dissociation-enhanced lanthanide fluorescent immunoassay, ATP matrix assays, and mTOR immune-complex kinase assays are performed. Assays of PI3Ks are performed. hSMG1 and ATR are assayed using glutathione S-transferase-p53 as a substrate, detected via DELFIA using an anti-P-p53 (S15) antibody. Assays of a panel of 230 protein kinases are performed[1]. |
| Cell Assay | Cell lines of MDA-MB-361, MDA-MB-231, MDA-MB-468, BT549, LNCap, A549, H1975, H157, H460, U87MG, A498, 786-O, HCT116, MG63, Rat1, HEK293, HeLa and PC3MM2 are used. MDA361 cells are treated for 3 d with CCI-779 and WYE-125132 (0.1 nM, 1 nM, 10 nM,100 nM, 1000 nM 10μM and 100μM). Cell growth assays and IC50 determination are performed. For immunoblotting, cultured cells are treated as indicated. Total cell lysates are prepared using NuPAGE lithium dodecyl sulfate sample buffer and immunoblotted with various antibodies[1]. |
| Animal Admin | Mice[1] For mTOR biomarker studies, various tumors (400 mm3) grown s.c. in female nude mice are dosed by a single i.v. or oral injection with vehicle or WYE-125132 formulated in 5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400. Tumor lysates are prepared and immunoblotted. For efficacy studies, nude mice bearing U87MG, MDA361, H1975, A549, A498, or 786-O tumors are staged and randomized into treatment groups (n=10). Mice are dosed orally with vehicle or WYE-125132 following qd x5 cycle regimen (5 d on, 2 d off) for up to four cycles. Temsirolimus/CCI-779 is formulated as WYE-125132 and dosed i.v. once weekly. Bevacizumab is formulated in PBS and dosed i.p. via its clinical regimen (200 μg/mouse; once weekly). Tumor growth is monitored and analyzed. |
| References |
| Density | 1.6±0.1 g/cm3 |
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| Boiling Point | 650.2±55.0 °C at 760 mmHg |
| Molecular Formula | C27H33N7O4 |
| Molecular Weight | 519.595 |
| Flash Point | 347.0±31.5 °C |
| Exact Mass | 519.259399 |
| PSA | 119.15000 |
| LogP | 1.27 |
| Vapour Pressure | 0.0±1.9 mmHg at 25°C |
| Index of Refraction | 1.764 |
| Storage condition | -20℃ |
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1144068-46-1 |
| Literature: Bioorganic and Medicinal Chemistry Letters, , vol. 20, # 4 p. 1440 - 1444 |
| Precursor 3 | |
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| DownStream 0 | |