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
-
- Apoptosis/drug effects
- Recombinant Proteins/metabolism
- Female
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Disease Models, Animal
- 2-Aminopurine/analogs & derivatives*
- 2-Aminopurine/chemistry
- 2-Aminopurine/pharmacokinetics
- 2-Aminopurine/pharmacology
- 2-Aminopurine/therapeutic use
- Piperazines/chemistry
- Piperazines/pharmacokinetics
- Piperazines/pharmacology
- Piperazines/therapeutic use*
- G1 Phase/drug effects
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Pancreatic Neoplasms/drug therapy*
- Pancreatic Neoplasms/pathology
- Rats, Sprague-Dawley
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacokinetics
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Drug Evaluation, Preclinical*
- Humans
- src-Family Kinases/antagonists & inhibitors*
- src-Family Kinases/metabolism
- Cell Line, Tumor
- Zebrafish
- Animals
- Neoplasm Metastasis/pathology
- Signal Transduction/drug effects
- Cell Proliferation/drug effects
- Resting Phase, Cell Cycle/drug effects
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/pharmacokinetics
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use*
- Cell Cycle Checkpoints/drug effects
- Mice, Nude
- 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