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
Menée in vitro et in vivo, cette étude évalue l'intérêt d'un nouveau composé appelé SKLB1206, un inhibiteur d'EGFR, pour le traitement de cancers ayant développé une résistance aux premières générations d'inhibiteurs d'EGFR, notamment le gefitiniib et l'erlotinib
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.
http://mct.aacrjournals.org/content/early/2012/02/07/1535-7163.MCT-11-0679.abstract