title: Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3- morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo.
abstract: Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wang
authors.forename: Ren-Lin
authors.initials: RL
authors.lastname: Zheng
authors.forename: Heng-Xiu
authors.initials: HX
authors.lastname: Yan
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Cao
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Ze-Rong
authors.initials: ZR
authors.lastname: Wang
authors.forename: Pan
authors.initials: P
authors.lastname: Ji
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Yang
authors.forename: Li-Jiao
authors.initials: LJ
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Liu
authors.forename: Jiao
authors.initials: J
authors.lastname: Yang
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Zhang
authors.forename: Shuang
authors.initials: S
authors.lastname: Ma
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Qi-Zheng
authors.initials: QZ
authors.lastname: Sun
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000627:therapeutic use*; D011799:Quinazolines / Q000138:chemical synthesis / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C573559:1-(5-(7-(3-morpholinopropoxy)quinazolin-4-ylthio)-(1,3,4)thiadiazol-2-yl)-3-p-tolylurea; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011799:Quinazolines; D013830:Thiadiazoles; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3