Journal
MOLECULAR CANCER THERAPEUTICS
Volume 11, Issue 4, Pages 952-962Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-11-0679
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Funding
- National Natural Science Foundation of China [81172987]
- National ST Major Project [2012ZX09102-101-002]
- SRFDP [20100181110025]
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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. Mol Cancer Ther; 11(4); 952-62. (C) 2012 AACR.
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