Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent

Cheng, Feng; Wang, Lingling; Shen, Yongchun; Xia, Jun; Chen, Heng; Jiang, Yuanqiang; Lu, Minyan

doi:10.1016/j.bbrc.2016.01.054

Cited by 6 publications

(8 citation statements)

References 28 publications

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“…Since WYE-687 is a novel mTOR kinase inhibitor[20,24], its effect on mTOR signaling was tested. As shown in Fig 4A, treatment with WYE-687 (100 nM, 2 hours) in 786-ORCC cells almost completely blocked phosphorylation (“p-”) of Akt (Ser-473), S6K1 (Thr-389) and S6 (Ser-235/236).…”

Section: Resultsmentioning

confidence: 99%

“…Within three weeks, the xenograft RCC tumors were established with the average tumor volumes of 100 mm 3 . Half of the mice were treated with WYE-687 (25 mg/kg body weight, oral gavage, daily, for 15 days)[20,24]. The other half mice were administrated with vehicle control (5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400) [24].…”

Section: Resultsmentioning

confidence: 99%

“…Half of the mice were treated with WYE-687 (25 mg/kg body weight, oral gavage, daily, for 15 days)[20,24]. The other half mice were administrated with vehicle control (5% ethanol, 2% Tween 80, and 5% polyethylene glycol-400) [24]. As demonstrated in Fig 5A, 786-O tumor growth in the WYE-687-administrated mice was significantly slower than that of vehicle control mice.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were treated with applied WYE-687 in the presence of thymidine (1 μCi/mL, Sigma). Afterwards, cells were washed, and the cellular DNA was precipitated [24]. The aliquots were counted by liquid-scintillation spectrometry.…”

Section: Methodsmentioning

confidence: 99%

“…Within three week, the tumor xenografts were established, and the tumor volumes were around 100 mm 3 . Mice (n = 10 each group) were treated once daily by gavage with either vehicle control or WYE-687 (25 mg/kg body weight) for 15 consecutive days[20,24]. Mice body weight and bi-dimensional tumor measurements were taken every 5 days.…”

Section: Methodsmentioning

confidence: 99%

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Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo

Pan

Mao

et al. 2017

PLoS ONE

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Mammalian target of rapamycin (mTOR)in renal cell carcinoma (RCC) represents a valuable oncotarget for treatment. We here tested the potential anti-RCC activity by a novel mTOR kinase inhibitor WYE-687in vitro and in vivo.WYE-687 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. Yet, it was non-cytotoxic toHK-2 tubular epithelial cells.WYE-687 provoked caspase-dependent apoptosis in the RCC cells. At the molecular level, WYE-687 almost completely blocked mTORC1 (p-S6K1 and p-S6) and mTORC2 (p-Akt Ser 473) activation in both 786-Ocells and primary human RCC cells, where it downregulated both hypoxia-inducible factor (HIF)-1α and HIF-2α expression. Significantly, oral administration of WYE-687 potently suppressed786-O tumor xenograft growth in nude mice. mTORC1/2 activation and HIF-1α/2α expression were also remarkably downregulated in WYE-687-treated tumor tissues. Thus, our preclinical results imply that WYE-687 may have important translational value for the treatment of RCC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo

Pan

Mao

et al. 2017

PLoS ONE

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The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415

Zhang¹,

Chen

et al. 2017

Biochemical and Biophysical Research Communications

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Recent advances in targeting mTOR signaling pathway using small molecule inhibitors

Roohi

Hojjat‐Farsangi

2016

Journal of Drug Targeting

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Targeted-based cancer therapy (TBCT) or personalized medicine is one of the main treatment modalities for cancer that has been developed to decrease the undesirable effects of chemotherapy. Targeted therapy inhibits the growth of tumor cells by interrupting with particular molecules required for tumorigenesis and proliferation of tumor cells rather than interfering with dividing normal cells. Therefore, targeted therapies are anticipated to be more efficient than former tumor treatment agents with minimal side effects on non-tumor cells. Small molecule inhibitors (SMIs) are currently one of the most investigated anti-tumor agents of TBCT. These small organic agents target several vital molecules involved in cell biological processes and induce target cells apoptosis and necrosis. Mechanistic (mammalian) target of rapamycin (mTOR) complexes (mTORC1/2) control different intracellular processes, including growth, proliferation, angiogenesis and metabolism. Signaling pathways, in which mTOR complexes are involved in are usually dysregulated in various tumors and have been shown to be ideal targets for SMIs. Currently, different mTOR-SMIs are in the clinic for the treatment of cancer patients, and several others are in preclinical or clinical settings. In this review, we summarize recent advances in developing different mTOR inhibitors, which are currently in preclinical and clinical investigations or have been approved for cancer treatment.

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Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent

Cited by 6 publications

References 28 publications

Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo

Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo

The anti-hepatocellular carcinoma cell activity by a novel mTOR kinase inhibitor CZ415

Recent advances in targeting mTOR signaling pathway using small molecule inhibitors

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