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.
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.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, China.
Youli
Y
Pan
Yong
Y
Xu
Shan
S
Feng
Shidong
S
Luo
Renlin
R
Zheng
Jiao
J
Yang
Lijiao
L
Wang
Lei
L
Zhong
Han-Yu
HY
Yang
Bing-Lin
BL
Wang
Yang
Y
Yu
Jingjing
J
Liu
Zhixing
Z
Cao
Xiaoyan
X
Wang
Pan
P
Ji
Zerong
Z
Wang
Xin
X
Chen
Shuang
S
Zhang
Yu-Quan
YQ
Wei
Sheng-Yong
SY
Yang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D047428:Protein Kinase Inhibitors; D011687:Purines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D040301:Vascular Endothelial Growth Factor Receptor-2; C575621:SKLB1206; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat