title: A novel anticancer diarylurea derivative HL-40 as a multi-kinases inhibitor with good pharmacokinetics in Wistar rats.
abstract: 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, PDGFRβ 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.
authors: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Yu-Yin
authors: YY
authors: Lu
authors: Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors: Cui-Rong
authors: CR
authors: Zhao
authors: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Rui-Qi
authors: RQ
authors: Wang
authors: School of Medicine and Pharmacy, Marine Drug R&D Department QMBRI, Ocean University of China, Qingdao 26603, China. Electronic address: wbli@ouc.edu.cn.
authors: Wen-Bao
authors: WB
authors: Li
authors: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. Electronic address: qxj@sdu.edu.cn.
authors: Xian-Jun
authors: XJ
authors: Qu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057075:Enzyme Assays; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017208:Rats, Wistar; D014508:Urea / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; C000602101:N-(4-(1-(4-chloroindazole))phenyl)-N-(4-chloro-3-trifluoromethylphenyl)urea; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D014508:Urea
keywords: Anti-tumor activities; Binding constants (K(d)); Diarylurea derivative; HL-40; Kinases activities; Pharmacokinetics