The receptor tyrosine kinase c-Met, also known as receptor of hepatocyte growth factor (HGF) and scatter factor, plays an important role in physiologic processes such as embryologic development, wound healing, tissue regeneration, angiogenesis, cell growth, local invasion, and morphogenetic differentiation[3]. And its downstream v-akt murine thymoma viral oncogene homolog (AKT) and mitogen-activated protein kinase (ERK) pathways are regulated by HGF/c-MET. The HGF/c-MET axis is involved in cancer progression, metastasis, and acquired resistance[4]. JNJ-38877605 is an orally available, nanomolar active and highly selective c-Met ATP-competitive kinase inhibitor with IC50 of 4.7 nM for c-Met kinase, which induces cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-MET protein, and it also can suppress the phosphorylation of Ron[5]. After JNJ-38877605 totally was dosed 200, 300 and 350 mg/kg per week for 1 month at rabbits, renal toxicity had been observed[6]. In an experiment, a kind of deuterated JNJ-38877605 was administrated 10 mg/kg to cynomolgus monkeys, suggesting that deuterated JNJ-38877605 displayed diminished renal toxicity[7]. In a vitro study, EBC1 (NSCLCs), GTL16, NCI-H1993, and MKN45 (gastric adenocarcinomas) cell lines were treated with c-Met selective inhibitor JNJ-38877605 at a dose of 500 nM for 2h, as it is expected that JNJ-38877605 caused a significant reduction of Met phosphorylation[5]. In a vivo study, JNJ-3887760 were used to treat renal CSCs (cancer stem cells) mice implanted with a human bone at a dose of 40 mg/kg for 60 days, and it was showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases[8].
作用机制
JNJ-38877605 binds to the ATP-binding site of c-Met kinase with a high affinity.
JNJ-38877605 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
human EBC1 cells
Proliferation assay
72 h
Antiproliferative activity against human EBC1 cells after 72 hrs, IC50=9.5 nM
26005523
human MKN45 cells
Proliferation assay
72 h
Antiproliferative activity against human MKN45 cells after 72 hrs, IC50=10.9 nM
26005523
human SNU5 cells
Proliferation assay
72 h
Antiproliferative activity against human SNU5 cells after 72 hrs, IC50=15.8 nM
26005523
mouse BAF3/TPR-Met cells
Proliferation assay
72 h
Antiproliferative activity against mouse BAF3/TPR-Met cells after 72 hrs, IC50=17.6 nM
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