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Search results for: XL-765 (SAR-245409) Mechanisms: PI3K mTOR inhibitor

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#31360067   2019/07/08 To Up

Dual PI3K/mTOR Inhibitor, XL765, suppresses glioblastoma growth by inducing ER stress-dependent apoptosis.

Deregulated phosphoinositide 3-kinase (PI3K)/mTOR signaling commonly exists in glioblastoma (GBM), making this axis an attractive target for therapeutic manipulation. A recent dual inhibitor of PI3K/mTOR pathway, XL765, exhibited an attractive suppression effect on GBM tumor growth. However, the exact functional mechanisms of tumor suppression mediated by XL765 have not yet been fully characterized. In this study, we took efforts to assess the effects of PI3K/mTOR blockade by XL765 on GBM growth and . We analyzed the cytotoxicity of XL765 in three different GBM cell lines, A172, U87MG, and T98G, by using Hoechst 33258 (Invitrogen), Annexin V/propidium iodide (PI), as well as Cell Counting Kit -8 (CCK-8) assay. We also used A172 xenograft model to study the effect of XL765 . We found that XL765 inhibits GBM viability with a wide range of potencies. Importantly, XL765 suppressed GBM cell growth by inducing endoplasmic reticulum (ER) stress dependent apoptosis. The activation of CHOP/DR5 pathway by XL765 induced ER stress is responsible for the induction of apoptosis. Moreover, the inhibition of mTOR signal by XL765 is the major source of ER stress, rather than inhibition of PI3K. At last, we demonstrated that combination of XL765 with GMB chemotherapeutic drug, temozolomide (TMZ), can achieved better therapy effect and . Overall, our data show that targeting PI3K/mTOR by XL765 is a promising therapeutic strategy to relieve tumor burden in GBM patients.
Hang Zhao, Guangyong Chen, Huaxin Liang

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#31247018   2019/06/27 To Up

Anticancer compound XL765 as PI3K/mTOR dual inhibitor: A structural insight into the inhibitory mechanism using computational approaches.

The PI3K-AKT-mTOR pathway is often a commonly disrupted pathway in human cancer and, therefore, it is widely exploited for cancer therapy. The inhibitors for the important proteins of the pathway including PI3K and mTOR have been increasingly designed. The dual inhibitors targeting PI3K and mTOR both have proven to be more effective than those targeting single protein only. An orally-active compound XL765 is well established as PI3K/mTOR dual inhibitor and have shown in vitro and in vivo anticancer activity against a variety of cancer types and is undergoing clinical trials. The present study explored the exact binding pose and the the interactive forces holding XL765 within the active sites of PI3Kγ and mTOR using molecular docking analyses. The XL765 interacting residues of both the proteins were delineated and the degree of participation in binding was estimated by various methods. In the process, among the interacting residues of PI3Kγ, the Lys-890 and the Met-953 were recognized as the key residues involved in XL765 binding. While, in mTOR case, the Trp-2239 was recognized as the key residue playing role in the XL765 binding. In order to explore the better inhibitors, the study also generated combinatorial chemical library by modifying the scaffold considered from XL765. The virtual screening of the generated compound library led to identification of six novel promising compounds proposed as PI3K/mTOR dual inhibitors. Thus, the present work will through light on the drug inhibitory mechanism of XL765 for PI3K and mTOR, and will also assist in designing novel efficacious drug candidates.
Mohd Rehan

2965 related Products with: Anticancer compound XL765 as PI3K/mTOR dual inhibitor: A structural insight into the inhibitory mechanism using computational approaches.

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#31204923   // To Up

[Effect of PI3K/mTOR Signal Pathway Inhibitor XL765 on Human Leukemic KG-1 Cells].

To explore the effect and possible mechanism of PI3K/mTOR inhibitor XL765 on KG-1 cells in vitro.
Pin Wu, Su-Ning Chen, Qian Wang, Chuan He, Ri Zhang

2756 related Products with: [Effect of PI3K/mTOR Signal Pathway Inhibitor XL765 on Human Leukemic KG-1 Cells].

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