AZD8055 is a novel ATP-competitive inhibitor of mTOR kinase (both complexes mTORC1 and mTORC2) with an IC50 of 0.8 nM.Particularly,AZD8055 fully inhibited multisite eIF4E-binding protein1 phosphorylation,subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells.
|Cell lines||H838 and A549 cells line|
|Preparation method||Growth inhibition and autophagy analysis. For growth inhibition and acridine staining, cells were exposed to increasing concentrations of AZD8055 for 72 to 96 h and stained for cell nuclei (0.03 mg/mL Hoechst 33342) and acidic vesicles (1 μg/mL acridine orange). Images were captured at 450 and 536 nm on an ArrayScan II (Cellomics) platform, and the percentage of acidic vesicles and the number of cells were quantified. For LC3 assessment, cells were exposed to e64d/pepstatin (10 μg/mL) for 30 to 90 min before incubation with AZD8055. Cells were lysed on ice and analyzed by immunoblotting.|
|Incubation time||72~96 h|
|Animal models||Mice bearing U87-MG xenografts or A549 xenografts|
|Formulation||dissolved in captisol (CyDex) and diluted to a final captisol concentration of 30% (w/v)|
|Dosages||0.1 mL/10 g of body weight once or twice daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Proc Natl Acad Sci U S A. (2015). Figure 3. ABT-263 and AZD8055 were purchased from Active Biochemicals (Hong Kong, China) and Abmole Bioscience (Houston, TX)|
|Method||FACS analysis(Apoptosis), Western blotting, Immunoprecipitation (IP),Traditional human cell-line xenograft experiments|
|Cell Lines||SCLC H82 and H1048 cells|
|Concentrations||500 nM AZD8055, 1 μM ABT-263|
|Incubation Time||2,16, 72h|
|Results||Combination treatment with ABT-263 and the TORC1/2 inhibitor AZD8055 leads to robust apoptosis and antitumor activity in vivo.|
|Source||Proc Natl Acad Sci U S A. (2015). Figure 2. ABT-263 and AZD8055 were purchased from Active Biochemicals (Hong Kong, China) and Abmole Bioscience (Houston, TX)|
|Method||FACS analysis(Apoptosis),quantitative (q)RT-PCR, Western blotting, Immunoprecipitation (IP)|
|Cell Lines||SCLC SW1271 and H1048 cells|
|Results||BIM and MCL-1 mediate ABT-263–induced apoptosis in SCLC, and the ratio of BIM to MCL-1 expression predicts the magnitude of apoptosis in SCLC cell lines.|
|Source||Proc Natl Acad Sci U S A. (2015). Figure 1. ABT-263 and AZD8055 were purchased from Active Biochemicals (Hong Kong, China) and Abmole Bioscience (Houston, TX)|
|Cell Lines||SCLC cell lines|
|Results||we found a modest, but significant, correlation between BIM expression and sensitivity to ABT-263.ABT-263 across both data sets (SI Appendix, Fig. S1 B and C). However, the ratio of BIM to MCL-1 predicted sensitivity to ABT-263 more effectively than the expression of either biomarker alone. SCLC lines have increased BIM expression compared with other solid tumor types along with enhanced sensitivity to ABT-263 compared with other solid tumor types across a large panel of cancer cell lines.|
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1288-96.
Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study.
Asahina et al. Invest New Drugs. 2012 Jul 28. PMID: 22843211.
Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).
Holt et al. Cancer Res. 2012 Apr 1;72(7):1804-13. PMID: 22271687.
|Related mTOR Products|
Zotarolimus (ABT-578) is an analogue of rapamycin, and inhibits FKBP-12 binding with IC50 of 2.8 nM.
LY303511 is a structural analogue of LY294002, which does not inhibit PI3K, increased homotypic GJIC.
Temsirolimus (CCI-779) is a specific mTOR inhibitor with IC50 of 1.76 μM.
WYE-125132 is a highly potent, ATP-competitive mTOR inhibitor with IC50 of 0.19 nM; highly selective for mTOR versus PI3Ks or PI3K-related kinases hSMG1 and ATR.
AZD2014 is a novel dual mTORC1 and mTORC2 inhibitor with potential antineoplastic activity.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2017 AbMole BioScience. All Rights Reserved.