Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K).
Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K).
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DOI：
10.1021/acs.jmedchem.5b01655
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发表时间：
2016-03-24
影响因子：
7.3
通讯作者：
Ross BD
中科院分区：
文献类型：
--
作者：
Van Dort ME;Hong H;Wang H;Nino CA;Lombardi RL;Blanks AE;Galbán S;Ross BD
报道了一系列由结构类似物共价连接而成的单一实体双功能MEK1/PI3K抑制剂的合成方法。在体外的酶抑制实验中，抑制剂对MEK1(0.015)和PI3K(54)显示出较强的抑制作用。在两种肿瘤细胞系(A549、D54)中，抑制剂9和14同时抑制MEK1和PI3K。与同等剂量的ZSTK474和PD0325901联合给药时，抑制剂引起的细胞存活率呈剂量依赖性下降。口服14对D54胶质瘤和A549肺癌小鼠均有体内疗效。Western印迹分析显示，化合物14在给药后2 h对肿瘤细胞ERK1/2和Akt磷酸化的抑制率分别为95%和67%，证实了该双功能抑制策略对MEK1/PI3K联合抑制的生物利用度和有效性。
The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 < IC50 (nM) < 56.7) and PI3K (54 < IC50 (nM) < 341) in enzymatic inhibition assays. Concurrent MEK1 and PI3K inhibition was demonstrated with inhibitors 9 and 14 in two tumor cell lines (A549, D54). Inhibitors produced dose-dependent decreased cell viability similar to the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated in D54 glioma and A549 lung tumor bearing mice. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, at 2 h postadministration by Western blot analysis, confirming the bioavailability and efficacy of this bifunctional inhibitor strategy toward combined MEK1/PI3K inhibition.