Characterization of a Cdc42 protein inhibitor and its use as a molecular probe.
Characterization of a Cdc42 protein inhibitor and its use as a molecular probe.
复制标题
DOI：
10.1074/jbc.m112.435941
复制
发表时间：
2013-03-22
期刊：
影响因子：
--
通讯作者：
Wandinger-Ness A
中科院分区：
文献类型：
--
作者：
Hong L;Kenney SR;Phillips GK;Simpson D;Schroeder CE;Nöth J;Romero E;Swanson S;Waller A;Strouse JJ;Carter M;Chigaev A;Ursu O;Oprea T;Hjelle B;Golden JE;Aubé J;Hudson LG;Buranda T;Sklar LA;Wandinger-Ness A
背景资料：通过整合细胞外信号与肌动蛋白细胞骨架的变化，Cdc 42在细胞生理学中起着重要作用，并与人类疾病有关。结果：在生化和细胞实验中发现一种小分子选择性抑制Cdc 42。结论：该化合物是一种高度选择性的Cdc 42抑制剂。意义：所描述的一流Cdc 42 GTP酶选择性抑制剂将在药物发现和基础研究中应用。cdc 42在细胞骨架组织、细胞周期进程、信号转导和囊泡运输中起重要作用。过度活跃的Cdc 42与癌症、免疫疾病和神经元疾病的病理学有关。因此，Cdc 42抑制剂可用于探测分子通路，并可能具有治疗潜力。以前的抑制剂缺乏选择性，并倾向于毒性。我们在这里报告的Cdc 42-选择性鸟嘌呤核苷酸结合铅抑制剂，确定了高通量筛选的表征。通过结构-活性关系研究鉴定了第二活性类似物。这些化合物表现出优异的选择性，对同一GTdR家族中的Rho和Rac没有抑制作用。生化特性表明，化合物作为非竞争性变构抑制剂。当在细胞测定中测试时，先导化合物抑制Cdc 42相关的丝状伪足形成和细胞迁移。该先导化合物还用于阐明Cdc 42参与Sin Nombre病毒内化和整合素VLA-4的信号传导途径。总之，这些数据呈现了一种新型Cdc 42选择性变构抑制剂和相关类似物的表征，其使用将促进靶向Cdc 42相关疾病的药物开发和涉及GTP酶的分子途径研究。
Background: By integrating extracellular signals with actin cytoskeletal changes, Cdc42 plays important roles in cell physiology and has been implicated in human diseases. Results: A small molecule was found to selectively inhibit Cdc42 in biochemical and cellular assays. Conclusion: The identified compound is a highly Cdc42-selective inhibitor. Significance: The described first-in-class Cdc42 GTPase-selective inhibitor will have applications in drug discovery and fundamental research. Cdc42 plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. Therefore, Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential. Previous inhibitors have lacked selectivity and trended toward toxicity. We report here the characterization of a Cdc42-selective guanine nucleotide binding lead inhibitor that was identified by high throughput screening. A second active analog was identified via structure-activity relationship studies. The compounds demonstrated excellent selectivity with no inhibition toward Rho and Rac in the same GTPase family. Biochemical characterization showed that the compounds act as noncompetitive allosteric inhibitors. When tested in cellular assays, the lead compound inhibited Cdc42-related filopodia formation and cell migration. The lead compound was also used to clarify the involvement of Cdc42 in the Sin Nombre virus internalization and the signaling pathway of integrin VLA-4. Together, these data present the characterization of a novel Cdc42-selective allosteric inhibitor and a related analog, the use of which will facilitate drug development targeting Cdc42-related diseases and molecular pathway studies that involve GTPases.
GTPase Rho对T淋巴细胞形态的控制。
影响因子：
--
作者：
Woodside, DG;Wooten, DK;Teague, TK;Miyamoto, YJ;Caudell, EG;Udagawa, T;Andruss, BF;McIntyre, BW
通讯作者：
McIntyre, BW