Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization.
Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization.
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DOI：
10.1186/s12885-015-1415-6
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发表时间：
2015-05-28
期刊：
影响因子：
3.8
通讯作者：
Jaffe EK
中科院分区：
文献类型：
--
作者：
Ramirez UD;Nikonova AS;Liu H;Pecherskaya A;Lawrence SH;Serebriiskii IG;Zhou Y;Robinson MK;Einarson MB;Golemis EA;Jaffe EK
表皮生长因子受体（EGFR）的过表达或突变可有效促进许多实体瘤的生长。肿瘤细胞经常表现出对机械上不同的egfr导向治疗剂的耐药性，这使得开发通过其他机制起作用的治疗方法变得有价值。目前的egfr靶向治疗包括靶向细胞外结构域的抗体和抑制细胞内激酶结构域的小分子。最近的研究发现了一种新的细胞外四聚体EGFR结构，我们认为这是药物发现的潜在靶点。我们的重点是倾向于EGFR四聚体，它包含一种涉及细胞外结构域III的新型蛋白质蛋白质界面。这种EGFR四聚体是通过小分子配体结合来稳定的计算目标。这项研究对Life Chemicals， Inc.的345,232个药物样化合物的小分子文库进行了虚拟筛选，以对抗与新型四聚体不同的蛋白质-蛋白质界面的分子动力学模拟。通过基于细胞的高含量成像筛选，研究人员选择了109种化学成分不同的候选分子，并对其进行了评估，该筛选直接评估了EGFR效应蛋白Grb2的诱导内化。进一步评估阳性命中对EGFR及其效应物ERK1/2磷酸化的影响。14种被击中的化合物影响Grb2的内化，Grb2是一种响应EGFR激活的适配器。大多数撞击对细胞活力的影响有限，对EGFR和ERK1/2磷酸化的影响最小。对接的hit化合物位姿通常包括Arg270或邻近残基，它们也参与结合有效的治疗性西妥昔单抗，指导进一步的化学优化。这些数据表明，EGFR四聚体结构提供了一种新的癌症药物靶点。本文的在线版本（doi:10.1186/s12885-015-1415-6）包含补充材料，仅供授权用户使用。
Overexpression or mutation of the epidermal growth factor receptor (EGFR) potently enhances the growth of many solid tumors. Tumor cells frequently display resistance to mechanistically-distinct EGFR-directed therapeutic agents, making it valuable to develop therapeutics that work by additional mechanisms. Current EGFR-targeting therapeutics include antibodies targeting the extracellular domains, and small molecules inhibiting the intracellular kinase domain. Recent studies have identified a novel prone extracellular tetrameric EGFR configuration, which we identify as a potential target for drug discovery. Our focus is on the prone EGFR tetramer, which contains a novel protein-protein interface involving extracellular domain III. This EGFR tetramer is computationally targeted for stabilization by small molecule ligand binding. This study performed virtual screening of a Life Chemicals, Inc. small molecule library of 345,232 drug-like compounds against a molecular dynamics simulation of protein-protein interfaces distinct to the novel tetramer. One hundred nine chemically diverse candidate molecules were selected and evaluated using a cell-based high-content imaging screen that directly assessed induced internalization of the EGFR effector protein Grb2. Positive hits were further evaluated for influence on phosphorylation of EGFR and its effector ERK1/2. Fourteen hit compounds affected internalization of Grb2, an adaptor responsive to EGFR activation. Most hits had limited effect on cell viability, and minimally influenced EGFR and ERK1/2 phosphorylation. Docked hit compound poses generally include Arg270 or neighboring residues, which are also involved in binding the effective therapeutic cetuximab, guiding further chemical optimization. These data suggest that the EGFR tetrameric configuration offers a novel cancer drug target. The online version of this article (doi:10.1186/s12885-015-1415-6) contains supplementary material, which is available to authorized users.
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影响因子：
5.8
作者：
Hopper-Borge EA;Nasto RE;Ratushny V;Weiner LM;Golemis EA;Astsaturov I
通讯作者：
Astsaturov I
影响因子：
4.8
作者：
Lawrence, Sarah H.;Ramirez, Ursula D.;Jaffe, Eileen K.
通讯作者：
Jaffe, Eileen K.
影响因子：
11.5
作者：
Janjigian, Yelena Y.;Azzoli, Christopher G.;Riely, Gregory J.
通讯作者：
Riely, Gregory J.
DOI：
10.1073/pnas.0502860102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Kwak, EL;Sordella, R;Haber, DA
通讯作者：
Haber, DA
影响因子：
7.3
作者：
Astsaturov I;Ratushny V;Sukhanova A;Einarson MB;Bagnyukova T;Zhou Y;Devarajan K;Silverman JS;Tikhmyanova N;Skobeleva N;Pecherskaya A;Nasto RE;Sharma C;Jablonski SA;Serebriiskii IG;Weiner LM;Golemis EA
通讯作者：
Golemis EA