WYE-125132 (WYE-132)

WYE-125132 (WYE-132) is highly potent, ATP-competitive, and specific inhibitor of mTOR kinase with IC50 value of 0.19±0.07nmol/L, ＞5000-fold selective versus PI3Ks [1].

WYE-125132 (WYE-132) has been reported to mTORC1-dependent phosphorylation of S6K (T389) and mTORC2-dependent phos-phorylation of AKT (S473) in immune-complex assay. In addition, in insulin-like growth factor-I(IGF-I)–induced Rat1, the PIK3CA mutant MDA361, or PTEN-null U87MG cells, WYE-125132 (WYE-132) has also been revealed to dose-dependently inhibit P-S6K(T389) and P-AKT(S473) with EC50 in low nanomolar range. Apart from these, WYE-125132 (WYE-132) has shown a potent anti-proliferative agent against MDA361, PC3MM2, U87MG, A549, and HCT116 cell lines. Moreover, WYE-125132 (WYE-132) has noted a stronger inhibition of protein synthesis and cell size in MDA361 and HEK293 cell lines [1].

References:
[1] Yu K1, 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. 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):621-31. doi: 10.1158/0008-5472.CAN-09-2340. Epub 2010 Jan 12.

Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells.[Pubmed:20233713]

J Biol Chem. 2010 May 14;285(20):15380-92.

The mammalian target of rapamycin (mTOR) regulates growth via promoting translation and transcription. Here, employing an mTOR active-site inhibitor WYE-125132 (WYE-132), we have performed quantitative phospho-proteomics and identified a Ser-75-containing phosphopeptide from Maf1, a known repressor of RNA polymerase III (Pol III) transcription. Treatment of cancer cells with WYE-132 or the rapamycin analog CCI-779 led to a rapid loss of the phosphorylation at Ser-75, whereas this effect was not seen in cells treated with cytotoxic agents or unrelated inhibitors. WYE-132-induced Maf1 dephosphorylation correlated with its accumulation in the nucleus and a marked decline in the cellular levels of pre-tRNAs. Depletion of cellular Maf1 via small interfering RNA increased basal pre-tRNA and rendered tRNA synthesis refractory to mTOR inhibitors. Maf1 mutant proteins carrying S75A alone or with S60A, T64A, and S68A (Maf1-S75A, Maf1-4A) progressively enhanced basal repression of tRNA in actively proliferating cells and attenuated amino acid-induced tRNA transcription. Gene alignment revealed conservation of all four Ser/Thr sites in high eukaryotes, further supporting a critical role of these residues in Maf1 function. Interestingly, mTOR inhibition led to an increase in the occupancy of Maf1 on a set of Pol III-dependent genes, with concomitant reduction in the binding of Pol III and Brf1. Unexpectedly, mTORC1 itself was also enriched at the same set of Pol III templates, but this association was not influenced by mTOR inhibitor treatment. Our results highlight a new and unique mode of regulation of Pol III transcription by mTOR and suggest that normalization of Pol III activity may contribute to the therapeutic efficacy of mTOR inhibitors.

Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2.[Pubmed:20068177]

Cancer Res. 2010 Jan 15;70(2):621-31.

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.

WYE-132 (WYE-125132) is a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC50: 0.19±0.07 nM; >5,000-fold selective versus PI3Ks). WYE-132 (WYE-125132) inhibits mTORC1 and mTORC2.

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