PUBLICATION
A preclinical evaluation of SKLB261, a multi-kinase inhibitor of EGFR/Src/VEGFR2, as a therapeutic agent against pancreatic cancer
- Authors
- Pan, Y., Zheng, M., Zhong, L., Yang, J., Zhou, S., Qin, Y., Xiang, R., Chen, Y., Yang, S.Y.
- ID
- ZDB-PUB-141219-11
- Date
- 2015
- Source
- Molecular cancer therapeutics 14(2): 407-18 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- 2-Aminopurine/analogs & derivatives*
- 2-Aminopurine/chemistry
- 2-Aminopurine/pharmacokinetics
- 2-Aminopurine/pharmacology
- 2-Aminopurine/therapeutic use
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacokinetics
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Cell Cycle Checkpoints/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Disease Models, Animal
- Drug Evaluation, Preclinical*
- Female
- G1 Phase/drug effects
- Humans
- Mice, Nude
- Neoplasm Metastasis/pathology
- Pancreatic Neoplasms/drug therapy*
- Pancreatic Neoplasms/pathology
- Piperazines/chemistry
- Piperazines/pharmacokinetics
- Piperazines/pharmacology
- Piperazines/therapeutic use*
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/pharmacokinetics
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use*
- Rats, Sprague-Dawley
- Recombinant Proteins/metabolism
- Resting Phase, Cell Cycle/drug effects
- Signal Transduction/drug effects
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Zebrafish
- src-Family Kinases/antagonists & inhibitors*
- src-Family Kinases/metabolism
- PubMed
- 25519702 Full text @ Mol. Cancer Ther.
Citation
Pan, Y., Zheng, M., Zhong, L., Yang, J., Zhou, S., Qin, Y., Xiang, R., Chen, Y., Yang, S.Y. (2015) A preclinical evaluation of SKLB261, a multi-kinase inhibitor of EGFR/Src/VEGFR2, as a therapeutic agent against pancreatic cancer. Molecular cancer therapeutics. 14(2):407-18.
Abstract
The clinical prognosis of pancreatic cancer remains rather disappointing despite tremendous efforts in exploring medical treatments in the past two decades. Development of more effective treatment strategies is still desperately needed to improve outcomes in patients with pancreatic cancer. SKLB261 is a multi-kinase inhibitor obtained recently through a lead optimization (J. Med. Chem. 2012, 55, 10685-10699). In this investigation, we shall evaluate its anti-pancreatic cancer effects both in vitro and in vivo. SKLB261 is a multi-kinase inhibitor potently inhibiting EGFR, Src, and VEGFR2 kinases. It could significantly inhibit cell proliferation, migration, and invasion, and induce apoptosis, in cellular assays of human pancreatic cancer cells that are sensitive or resistant to dasatinib and/or gemcitabine. Western blot analysis showed that SKLB261 inhibited the activation of EGFR and Src kinases as well as their downstream signaling proteins including FAK, ERK, and STAT3. SKLB261 also showed potent anti-angiogenic effects in transgenic zebrafish models. In vivo, SKLB261 displayed more potent antitumor activities than dasatinib, gemcitabine, or erlotinib, in pancreatic cancer xenografts including BxPC-3, PANC-1, AsPC-1, and HPAC. Furthermore, mice receiving SKLB261 therapy showed significant survival advantage compared with vehicle-treated and gemcitabine-treated groups in an experimental metastasis model of pancreatic cancer. These data, together with the good pharmacokinetic properties and low toxicity of this compound, provide a rationale for the ongoing clinical evaluation of SKLB261 in the treatment of pancreatic cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping