SKLB1206, a novel orally available multikinase inhibitor targeting EGFR activating and T790M mutants, ErbB2, ErbB4, and VEGFR2, displays potent antitumor activity both in vitro and in vivo

• Published in: Molecular cancer therapeutics Vol. 11; no. 4; pp. 952 - 962
• Main Authors: Pan, Youli, Xu, Yong, Feng, Shan, Luo, Shidong, Zheng, Renlin, Yang, Jiao, Wang, Lijiao, Zhong, Lei, Yang, Han-Yu, Wang, Bing-Lin, Yu, Yang, Liu, Jingjing, Cao, Zhixing, Wang, Xiaoyan, Ji, Pan, Wang, Zerong, Chen, Xin, Zhang, Shuang, Wei, Yu-Quan, Yang, Sheng-Yong
• Format: Journal Article
• Language: English
• Published: United States 01.04.2012
• Subjects: 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, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; 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
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-11-0679

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 oncokinases, including ErbB2, ErbB4, and VEGF receptor 2 (VEGFR2). SKLB1206 exhibited highly antiproliferative 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 antiangiogenesis effect in vitro, in a zebrafish embryonic angiogenesis assay, and in an alginate-encapsulate tumor cell assay. In vivo, oral administration of SKLB1206 showed 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.