國家衛生研究院 NHRI:Item 3990099045/7001
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    题名: BPR1J271, a novel FLT3 inhibitor for treating acute myeloid leukemia
    作者: Chen, CT;Lin, WH;Chou, LH;Chen, CP;Yen, SC;Huang, YL;Yeh, TK;Hsu, JTA;Jiaang, WI;Chao, YS
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Background: Acute myeloid leukemia (AML) is the most common type of leukemia in adults. FLT3 (FMS-like tyrosine kinase 3), a cell surface receptor belonging to the class III receptor tyrosine kinase family, plays a pivotal role in differentiation and survival of the hematopoietic stem cells in bone marrow. FLT3 kinase is frequently over-expressed and mutated in AML patients. Mutations of FLT3 resulting in constitutive phosphorylation and activation of FLT3 lead to subsequent activation of downstream signal molecules. FLT3-ITD is a frequent mutation in AML and associated with poor prognosis in AML patients. FLT3 is a promising molecular drug target for development of inhibitors as therapeutics for treating AML. We have designed and synthesized a number of novel FLT3 inhibitors of small molecules with different chemical structural scaffolds. BPR1J271 (N-(5-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureidomethyl]-phenyl}-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-benzamide) has been identified with promising activities against AML. Material and Methods: Protein kinase activities were measured by using the Kinase-Glo? luminescent kinase assays. Western blot assay was applied to verify the levels of the targeted proteins in cancer cells and the cytotoxicity of BPR1J271 against human leukemia cells was assayed by colorimetric MTS/PMS method and its in vivo anticancer activities were evaluated using the subcutaneously xenografted growing tumors in nude mice i.v. treated with BPR1J271. Plasma concentrations of BPR1J271 i.v. administered to rats were measured and analyzed for pharmacokinetic parameters in rats. Results: We have discovered a novel small molecule BPR1J271 that exhibits potent inhibitory activities against FLT3 (IC50 = 18 nM) and FLT3-ITD (IC50 = 1 nM) kinases. BPR1J271 was also found active against a panel of selected protein tyrosine kinases, including AMPK A1/B1/G1, CSF1R (FMS) TRKA, RET, JAK1, TEK (Tie2) and TYK2. In addition, it also strongly inhibited the phosphorylation of STAT5 (IC50 = 1 nM). Furthermore, BPR1J271 showed potent growth inhibition activities on FLT3-ITDexpressing human leukemia MOLM-13 and MV4;11 cells with GI50 values of 2.7 and 2.3 nM, respectively. BPR1J271 exhibited significant i.v. dosedependent tumor growth inhibition and regression in MOLM-13 tumors subcutaneously growing in nude mice. A complete tumor growth regression was observed in 5 out of 7 treated tumors growing in nude mice. It also showed a pharmacokinetic property of suitable plasma half-life of 6 hr, clearance of 11 ml/min/kg and AUC exposure of 3145 ng/ml?hr in the rats. Conclusions: BPR1J271 has demonstrated promising in vitro and in vivo activity profiles inhibiting FLT3 kinase activity and leukemia cell growth. It has been identified as a drug lead/candidate for further developments for treating AML.
    日期: 2012-11
    關聯: European Journal of Cancer. 2012 Nov;48(Suppl. 6):53-54.
    Link to: http://dx.doi.org/10.1016/S0959-8049(12)71974-3
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0959-8049&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000312763000172
    显示于类别:[趙宇生(2002-2013)] 會議論文/會議摘要
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