WYE-132 (WYE-125132) 是一种高度有效的 ATP 竞争性和特异性 mTOR 激酶抑制剂 (IC₅₀ 为 0.19±0.07 nM)。WYE-132 (WYE-125132) 抑制 mTORC1 和 mTORC2。

WYE-132 (WYE-125132) is a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC 50 : 0.19±0.07 nM; >5,000-fold selective versus PI3Ks). WYE-132 (WYE-125132) inhibits mTORC1 and mTORC2.

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mTORC1 mTORC2

WYE-132 (WYE-125132) potently inhibits recombinant mTOR via an ATP-competitive mechanism. WYE-132 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-132 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-132 elicits a more profound increase in G1-phase and a reduction in S-phase cells than CCI-779. The WYE-132-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.

A single i.v. administration of 50 mg/kg WYE-132 (WYE-125132) 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-132 under such dosing regimens reflects the suppression of mTOR rather than PI3K. Oral administration of WYE-132 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-132 induces a substantial regression of large MDA361 tumors. WYE-132 also causes a potent and substantial tumor growth delay in the PTEN-null U87MG glioma.

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[1]. Yu K, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.Cancer Res. 2010 Jan 15;70(2):621-631.

In Vitro: DMSO : 25 mg/mL (48.11 mM; Need ultrasonic)配制储备液