A novel anticancer diarylurea derivative HL-40 as a multi-kinases inhibitor with good pharmacokinetics in Wistar rats

作者：Lu, Yu-Yin; Zhao, Cui-Rong; Wang, Rui-Qi; Li, Wen-Bao^*; Qu, Xian-Jun

来源：Biomedicine & Pharmacotherapy, 2015, 69: 255-259.

DOI：10.1016/j.biopha.2014.11.003

• HL-40
• Diarylurea derivative
• Kinases activities
• Binding constants (K-d)
• Pharmacokinetics
• Anti-tumor activities

HL-40, N-(4-(1-(4-chlorine indazole)) phenyl)-N-(4-chloro-3-three fluorine methyl phenyl) urea, is a novel diarylurea derivative. In this study, we investigated the kinases activities and binding constants, pharmacokinetics of HL-40, and then evaluated its anticancer efficacy by both in vitro and in vivo methods. Enzyme activities assays in vitro were employed to identify eight candidate kinase targets. The competition binding assays against eight candidate kinases suggested that HL-40 showed strong affinity to c-Kit, PDGFR beta and FLT3. The pharmacokinetic studies in Wistar rats showed that HL-40 could maintain high compound concentration and long residence time in the blood circulation. HL-40 possessed strong inhibition activities against 12 human cancer cells. Meanwhile, HL-40 effectively delayed the growth of cancer xenografts without significant toxicity to mice. Based on these in vitro and in vivo results, we suggested that HL-40 might be developed as a potential multi-kinases inhibitor for cancer treatment.

• 出版日期2015-2
• 单位山东大学; 中国海洋大学; 山东省立医院