SKLB1206, a novel orally available multi-kinase inhibitor targeting EGFR activating and T790M mutants, ErbB2, ErbB4 and VEGFR2, displays potent antitumor activity both in vitro and in vivo
- Authors
- Pan, Y., Xu, Y., Feng, S., Luo, S., Zheng, R., Yang, J., Wang, L., Zhong, L., Yang, H., Wang, B., Yu, Y., Liu, J., Cao, Z., Wang, X., Ji, P., Wang, Z., Chen, X., Zhang, S., Wei, Y.Q., and Yang, S.Y.
- ID
- ZDB-PUB-120215-9
- Date
- 2012
- Source
- Molecular cancer therapeutics 11(4): 952-962 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Humans
- Immunohistochemistry
- Male
- Mice
- Mice, Nude
- Mutation
- Phosphorylation
- Protein Kinase Inhibitors/pharmacology*
- Purines/pharmacology*
- Quinazolines/pharmacology
- Random Allocation
- Rats
- Rats, Sprague-Dawley
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-2/genetics
- Receptor, ErbB-4
- Signal Transduction/drug effects
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
- Vascular Endothelial Growth Factor Receptor-2/genetics
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 22319204 Full text @ Mol. Cancer Ther.
Anti-epidermal growth factor receptor (EGFR) treatment has been successfully applied in clinical cancer therapy. However, the clinical efficacy of first-generation reversible EGFR inhibitors, such as gefitinib and erlotinib, is limited by the development of drug-resistant mutations, including the gatekeeper T790M mutation and upregulation of alternative signaling pathways. Second-generation irreversible EGFR inhibitors that were designed to overcome the drug resistance due to the T790M mutation have thus far had limited success. Here we report a novel reversible EGFR inhibitor, SKLB1206, which has potent activity against EGFR with gefitinib-sensitive and resistant (T790M) mutations. In addition, SKLB1206 has also considerable inhibition potency against some other related onco-kinases, including ErbB2, ErbB4 and vascular endothelial growth factor receptor 2 (VEGFR2). SKLB1206 exhibited highly anti-proliferative activity against a range of EGFR mutant cell lines, including gefitinib-sensitive and resistant cell lines, and EGFR or ErbB2-overexpressing cell lines. SKLB1206 also showed a potent anti-angiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 demonstrated complete tumor regression in gefitinib-sensitive HCC827 and PC-9 xenograft models, and showed a considerable antitumor effect on the gefitinib-resistant H1975 model as well as other EGFR/ErbB2-overexpressing or -dependent tumor models including A431, LoVo and N87 established in athymic mice. SKLB1206 also showed a very good oral bioavailability (50.1%). Collectively, these preclinical evaluations may support clinical development of SKLB1206 for cancers with EGFR activating/resistance mutations or EGFR/ErbB2 overexpressed.