For research use only. Not for therapeutic Use.
WYE-132（Cat No.:I000541）is a potent and selective inhibitor of the mammalian target of rapamycin (mTOR), specifically targeting both mTORC1 and mTORC2 complexes. By inhibiting mTOR signaling, WYE-132 disrupts critical cellular processes such as growth, proliferation, and survival, making it a valuable tool in cancer research. Its dual inhibition enhances its potential to overcome resistance mechanisms found in tumors treated with traditional mTOR inhibitors. WYE-132 is used in preclinical studies to explore its therapeutic effects on various cancers and its role in regulating metabolic and immune pathways.
| Catalog Number | I000541 |
| CAS Number | 1144068-46-1 |
| Synonyms | 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 |
| Molecular Formula | C₂₇H₃₃N₇O |
| Purity | ≥95% |
| Target | mTOR |
| Solubility | DMSO: ≥ 62 mg/mL |
| Storage | -20°C Freezer |
| IC50 | 0.19 nM |
| IUPAC 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 |
| InChI | InChI=1S/C27H33N7O4/c1-28-26(35)30-18-4-2-17(3-5-18)23-31-24(33-15-20-6-7-21(16-33)38-20)22-14-29-34(25(22)32-23)19-8-10-27(11-9-19)36-12-13-37-27/h2-5,14,19-21H,6-13,15-16H2,1H3,(H2,28,30,35) |
| InChIKey | QLHHRYZMBGPBJG-UHFFFAOYSA-N |
| SMILES | CNC(=O)NC1=CC=C(C=C1)C2=NC3=C(C=NN3C4CCC5(CC4)OCCO5)C(=N2)N6CC7CCC(C6)O7 |
| Reference | 1:Cancer Res. 2010 Jan 15;70(2):621-31. doi: 10.1158/0008-5472.CAN-09-2340. Epub 2010 Jan 12. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.Yu K,Shi C,Toral-Barza L,Lucas J,Shor B,Kim JE,Zhang WG,Mahoney R,Gaydos C,Tardio L,Kim SK,Conant R,Curran K,Kaplan J,Verheijen J,Ayral-Kaloustian S,Mansour TS,Abraham RT,Zask A,Gibbons JJ, PMID: 20068177 DOI: 10.1158/0008-5472.CAN-09-2340 </br><span>Abstract:</span> The mammalian target of rapamycin (mTOR) is a major component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway that is dysregulated in 50% of all human malignancies. Rapamycin and its analogues (rapalogs) partially inhibit mTOR through allosteric binding to mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report WYE-125132 (WYE-132), a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC(50): 0.19 +/- 0.07 nmol/L; >5,000-fold selective versus PI3Ks). WYE-132 inhibited mTORC1 and mTORC2 in diverse cancer models in vitro and in vivo. Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT(S473) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT(T308), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells. Compared with the rapalog temsirolimus/CCI-779, WYE-132 elicited a substantially stronger inhibition of cancer cell growth and survival, protein synthesis, cell size, bioenergetic metabolism, and adaptation to hypoxia. Oral administration of WYE-132 to tumor-bearing mice showed potent single-agent antitumor activity against MDA361 breast, U87MG glioma, A549 and H1975 lung, as well as A498 and 786-O renal tumors. An optimal dose of WYE-132 achieved a substantial regression of MDA361 and A549 large tumors and caused complete regression of A498 large tumors when coadministered with bevacizumab. Our results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy. |
