tcsc0066 WYE-132

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.

IC50 & Target: IC50: 0.19±0.07 nM (mTOR), 1179 nM (PI3Kα), 2380 nM (PI3Kδ), 1250 nM (hSMG1)^[1]

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].