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Oncotarget. 2015 Oct 13;6(31):31272-83. doi: 10.18632/oncotarget.5211.

Phospho-kinase profile of colorectal tumors guides in the selection of multi-kinase inhibitors.

Author information

1
Translational Research Unit, Albacete University Hospital, Albacete, Spain.
2
Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
3
EntreChem S.L., Oviedo, Spain.

Abstract

Protein kinases play a central role in the oncogenesis of colorectal tumors and are attractive druggable targets. Detection of activated kinases within a tumor could open avenues for drug selection and optimization of new kinase inhibitors. By using a phosphokinase arrays with human colorectal tumors we identified activated kinases, including the Epidermal Growth Factor Receptor (EGFR), components of the PI3K/mTOR pathway (AKT and S6), and STAT, among others. A pharmacological screening with kinase inhibitors against these proteins helped us to identify a new kinase inhibitor, termed EC-70124 that showed the highest anti-proliferative activity in cell lines. EC-70124 also inhibited cell migration and biochemical experiments demonstrated its effect targeting the PI3K/mTOR pathway. This drug also arrested cells at G2/M and induced apoptosis. Experiments in combination with standard chemotherapy used in the clinical setting indicated a synergistic effect. EC-70124 also reduced tumor growth in vivo and inhibited pS6 in the implanted tumors. In conclusion, by studying the kinase profile of colorectal tumors, we identified relevant activated pathways, and a new multi-kinase compound with significant antitumor properties.

KEYWORDS:

EC-70124; colon cancer; kinase inhibitors

PMID:
26418718
PMCID:
PMC4741604
DOI:
10.18632/oncotarget.5211
[Indexed for MEDLINE]
Free PMC Article

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