TY - JOUR
T1 - Bioinformatics-based discovery and characterization of an AKT-selective inhibitor 9-chloro-2-methylellipticinium acetate (CMEP) in breast cancer cells
AU - Zhang, Manchao
AU - Fang, Xueliang
AU - Liu, Hongpeng
AU - Guo, Ribo
AU - Wu, Xiaojin
AU - Li, Bihua
AU - Zhu, Feng
AU - Ling, Yan
AU - Griffith, Brian N.
AU - Wang, Shaomeng
AU - Yang, Dajun
N1 - Funding Information:
This work was supported in part by Department of Defense. CMEP was provided by Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD.
PY - 2007/7/18
Y1 - 2007/7/18
N2 - AKT is a promising target for anticancer drug development. In this work, a bioinformatics approach was applied to search for AKT inhibitors based on the correlation analysis between phospho-Ser473 AKT expression level and the antiproliferative data of NCI small molecule compounds against NCI 60 cancer cell lines, the candidate compounds were then subject to AKT kinase assay. The possible effects of potent compound on PI3K/AKT, PDK1, and MAPK, its antiproliferative and apoptosis-inducing effects on breast cancer cells which have high-levels of AKT activation were assessed by Western blot analysis, cell viability assay, and apoptosis assay. One compound, CMEP (NSC632855, 9-chloro-2-methylellipticinium acetate) was identified with all three correlation algorithm, Pearson's, Sperman's, and Kendall's, showing a high-ranked correlation coefficient. CMEP inhibits only AKT, but does not inhibit PI3K, PDK1, or MAPK. CMEP also inhibits heregulin-induced AKT activation, does not inhibit heregulin-induced MAPK activation in MCF-7 breast cancer cells. Increased concentrations of ATP reverse the AKT inhibitory effect of CMEP. CMEP inhibits growth and induces apoptosis in breast cancer cells which have high-levels of AKT activation and lack functional PTEN; however, CMEP only shows a minimal activity in NIH3T3 cells which do not have AKT activation. In conclusion, a lead compound CMEP, as an AKT selective inhibitor has been identified started with a bioinformatics-based approach. CMEP inhibits growth and induces apoptosis in cancer cells which have high-levels of AKT activation and lack PTEN or harbor PTEN mutation.
AB - AKT is a promising target for anticancer drug development. In this work, a bioinformatics approach was applied to search for AKT inhibitors based on the correlation analysis between phospho-Ser473 AKT expression level and the antiproliferative data of NCI small molecule compounds against NCI 60 cancer cell lines, the candidate compounds were then subject to AKT kinase assay. The possible effects of potent compound on PI3K/AKT, PDK1, and MAPK, its antiproliferative and apoptosis-inducing effects on breast cancer cells which have high-levels of AKT activation were assessed by Western blot analysis, cell viability assay, and apoptosis assay. One compound, CMEP (NSC632855, 9-chloro-2-methylellipticinium acetate) was identified with all three correlation algorithm, Pearson's, Sperman's, and Kendall's, showing a high-ranked correlation coefficient. CMEP inhibits only AKT, but does not inhibit PI3K, PDK1, or MAPK. CMEP also inhibits heregulin-induced AKT activation, does not inhibit heregulin-induced MAPK activation in MCF-7 breast cancer cells. Increased concentrations of ATP reverse the AKT inhibitory effect of CMEP. CMEP inhibits growth and induces apoptosis in breast cancer cells which have high-levels of AKT activation and lack functional PTEN; however, CMEP only shows a minimal activity in NIH3T3 cells which do not have AKT activation. In conclusion, a lead compound CMEP, as an AKT selective inhibitor has been identified started with a bioinformatics-based approach. CMEP inhibits growth and induces apoptosis in cancer cells which have high-levels of AKT activation and lack PTEN or harbor PTEN mutation.
KW - AKT
KW - Apoptosis
KW - Bioinformatics
KW - Growth
KW - Small molecules
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U2 - 10.1016/j.canlet.2006.12.035
DO - 10.1016/j.canlet.2006.12.035
M3 - Article
C2 - 17293030
AN - SCOPUS:34249286598
SN - 0304-3835
VL - 252
SP - 244
EP - 258
JO - Cancer Letters
JF - Cancer Letters
IS - 2
ER -