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Biological Activity
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Description
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XL765 is a dual inhibitor of mTOR/PI3k for mTOR, p110α, p110β, p110γ and p110δ with IC50 of 157 nM, 39 nM, 113 nM, 9 nM and 43 nM, respectively. |
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Targets
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mTOR |
p110α |
p110β |
p110γ |
p110δ |
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IC50 |
157 nM |
39 nM |
113 nM |
9 nM |
43 nM [1] |
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In Vitro
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XL765 is active against class I PI3K (IC50 = 39, 113, 9 and 43 nM for p110α, β, γ and δ, respectively). XL765 also inhibits DNA-PK (IC50 = 150 nM) and mTOR (IC50 = 157 nM) but not XL-147 which shows IC50 values of > 15 μM. [1] XL765 treatment results in decreased cell viability in 13 PDA cell lines in a dose-dependent manner. XL765, a dual-target PI3K/mTOR inhibitor, inhibits cell growth and apoptosis in many more cell lines and at lower concentrations as compared to the PI3K-selective inhibitors XL147 and PIK90. The effect can be recapitulated by using combinations of single-targeted compounds. XL765 significantly reduces phosphorylation of the mTOR targets S6, S6K, and 4EBP1, which is associated with greater apoptosis induction rather than to PI3K inhibition alone. XL765 treatment causes accumulation of autophagosomes in MIAPaCa-2 cells, and results in significant dose-dependent AVO induction and LC3-II stimulation in MIAPaCa-2 cells stably expressing a LC3-GFP construct. [2] |
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In Vivo
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The combination of XL765 (30 mg/kg) with chloroquine (50 mg/kg) results in significant inhibition of BxPC-3 xenograft growth in mice models, while XL765 alone at the same dose has no inhibitory effect. [2] Oral administration of XL765 results in greater than 12-fold reduction in median tumor bioluminescence compared to control and improvement in median survival in nude mice implanted intracranially with GBM 39-luc cells. XL765 in combination with temozolomide (TMZ) yields a 140-fold reduction in median bioluminescence with a trend toward improvement in median survival compared with TMZ alone. [3] |
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Clinical Trials
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A Phase I study to evaluate the safety and tolerability of XL765 in combination with erlotinib in subjects with solid tumors has been completed. |
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Features
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Protocol
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Kinase Assay
[1]
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Cell Assay
[2]
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| Cell Lines |
Pancreatic cancer cell lines (HcG25, Panc89, PA-TU8988T, Panc2.13, MiaPaCa2, Panc10.05, Panc8.13, BxPC-3, etc.) |
| Concentrations |
Dissolved in DMSO, final concentration ~10 μM |
| Incubation Time |
24, 48, 72 hours |
| Methods |
Cells are treated with XL765 24 hours after plating and harvested for apoptosis or autophagy assays at 24, 48, or 72 hours after XL765 treatment. Apoptosis is determined by total percentage of annexin V-positive cells by fluorescence-activated cell sorting (FACS). Acidic vesicular organelles (AVOs) are detected in XL765-treated cells by vital staining with acridine orange. The degree of AVO formation is expressed as fold increase of acridine orange fluorescence intensity (FL3) in XL765-treated cells versus control cells. |
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Animal Study
[2]
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| Animal Models |
Female Nu/Nu mice inoculated s.c. with BxPC-3 cells |
| Formulation |
Solubilized in water/10 mM HCl |
| Doses |
30 mg/kg |
| Administration |
Oral gavage once a day |
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References |
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[1] Garcia-Echeverria C, et al. Oncogene, 2008, 27(41), 5511-5526.
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[2] Mirzoeva OK, et al. J Mol Med, 2011, 89(9), 877-889.
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[3] Prasad G, et al. Neuro Oncol, 2011, 13(4), 384-392.
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