title: Discovery of novel N-(5-(tert-butyl)isoxazol-3-yl)-N'-phenylurea analogs as potent FLT3 inhibitors and evaluation of their activity against acute myeloid leukemia in vitro and in vivo.
abstract: FLT3 inhibitors have been explored as a viable therapy for acute myeloid leukemia (AML). However, the clinical outcomes of these FLT3 inhibitors were underwhelming except AC220. Therefore, the development of novel FLT3 inhibitors with high potency against both FLT3-WT and FLT3-ITD mutants are strongly demanded at the present time. In this study, we designed and synthesized a series of novel N-(5-(tert-butyl)isoxazol-3-yl)-N'-phenylurea derivatives as FLT3 inhibitors. SAR studies focused on the fused rings led to the discovery of a series of compounds with high potency against FLT3-ITD-bearing MV4-11 cells and significantly inhibitory activity toward FLT3. Among these compounds, N-(5-(tert-butyl)isoxazol-3-yl)-N'-(4-(7-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl)urea (16i), displayed acceptable aqueous solubility, desirable pharmacokinetic profile and high cytotoxicity selectivity against MV4-11 cells. This compound can inhibit phosphorylation of FLT3 and induce apoptosis in a concentration-dependent manner. Further in vivo antitumor studies showed that 16i led to complete tumor regression in the MV4-11 xenograft model at a dose of 60 mg/kg/d while without observable body weight loss. This study had provided us a new chemotype of FLT3 inhibitors as novel therapic candidates for AML.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Ning-Yu
authors.initials: NY
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Song
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Ting-Hong
authors.initials: TH
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: You
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Wei-Qiong
authors.initials: WQ
authors.lastname: Zuo
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
authors.forename: Li-Dan
authors.initials: LD
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: yuluot@scu.edu.cn.
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia; FMS-like tyrosine kinase 3 (FLT3); Inhibitor; N-(5-(tert-Butyl)isoxazol-3-yl)-N′-phenylurea