Enzymes最新文献_第7页

Ras chaperones: new targets for cancer and immunotherapy. Ras伴侣蛋白:癌症和免疫治疗的新靶点。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00012-9

Yoel Kloog, Galit Elad-Sfadia, Roni Haklai, Adam Mor

引用次数: 9

Targeting the Dbl and dock-family RhoGEFs: a yeast-based assay to identify cell-active inhibitors of Rho-controlled pathways. 靶向Dbl和dock家族RhoGEFs:一种基于酵母的测定方法，用于鉴定rho控制途径的细胞活性抑制剂。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00008-7

Anne Blangy, Philippe Fort

{"title":"Targeting the Dbl and dock-family RhoGEFs: a yeast-based assay to identify cell-active inhibitors of Rho-controlled pathways.","authors":"Anne Blangy, Philippe Fort","doi":"10.1016/B978-0-12-416749-0.00008-7","DOIUrl":"https://doi.org/10.1016/B978-0-12-416749-0.00008-7","url":null,"abstract":"The Ras-like superfamily of low molecular weight GTPases is made of five major families (Arf/Sar, Rab, Ran, Ras, and Rho), highly conserved across evolution. This is in keeping with their roles in basic cellular functions (endo/exocytosis, vesicular trafficking, nucleocytoplasmic trafficking, cell signaling, proliferation and apoptosis, gene regulation, F-actin dynamics), whose alterations are associated with various types of diseases, in particular cancer, neurodegenerative, cardiovascular, and infectious diseases. For these reasons, Ras-like pathways are of great potential in therapeutics and identifying inhibitors that decrease signaling activity is under intense research. Along this line, guanine exchange factors (GEFs) represent attractive targets. GEFs are proteins that promote the active GTP-bound state of GTPases and represent the major entry points whereby extracellular cues are converted into Ras-like signaling. We previously developed the yeast exchange assay (YEA), an experimental setup in the yeast in which activity of a mammalian GEF can be monitored by auxotrophy and color reporter genes. This assay was further engineered for medium-throughput screening of GEF inhibitors, which can readily select for cell-active and specific compounds. We report here on the successful identification of inhibitors against Dbl and CZH/DOCK-family members, GEFs for Rho GTPases, and on the experimental setup to screen for inhibitors of GEFs of the Arf family. We also discuss on inhibitors developed using virtual screening (VS), which target the GEF/GTPase interface with high efficacy and specificity. We propose that using VS and YEA in combination may represent a method of choice for identifying specific and cell-active GEF inhibitors. ","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"169-91"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/B978-0-12-416749-0.00008-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32513123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

The allosteric switch and conformational states in Ras GTPase affected by small molecules. 小分子对Ras GTPase变构开关和构象状态的影响。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00003-8

Christian W Johnson, Carla Mattos

引用次数: 33

State 1(T) inhibitors of activated Ras. 激活Ras的状态1(T)抑制剂。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00004-X

Hans Robert Kalbitzer, Michael Spoerner

引用次数: 13

Preface. 前言。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.10000-4

Fuyuhiko Tamanoi

引用次数: 0

Inhibitors of K-Ras plasma membrane localization. K-Ras质膜定位抑制剂。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00011-7

Kwang-Jin Cho, Dharini van der Hoeven, John F Hancock

引用次数: 13

Sugar-based inhibitors of Ras activation: biological activity and identification of Ras-inhibitor binding interface. 糖基Ras活化抑制剂:生物活性及Ras-抑制剂结合界面的鉴定。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00005-1

Alessandro Di Domizio, Francesco Peri

{"title":"Sugar-based inhibitors of Ras activation: biological activity and identification of Ras-inhibitor binding interface.","authors":"Alessandro Di Domizio, Francesco Peri","doi":"10.1016/B978-0-12-416749-0.00005-1","DOIUrl":"https://doi.org/10.1016/B978-0-12-416749-0.00005-1","url":null,"abstract":"Inhibition of oncogenic Ras activation through small molecules is a promising approach to the pharmacologic treatment of human tumors. A common strategy to block Ras activation and signal transduction is based on molecules that interfere with the guanine exchange factors (GEF)-promoted nucleotide exchange. We developed several generations of small molecules active in inhibiting Ras activation at low micromolar concentrations. Some of these compounds are more active on cell lines expressing oncogenic Ras than on normal cells and are therefore good hit compounds for anticancer drug development. The molecules belonging to the last generation are soluble in water and allowed the identification of binding site on Ras by means of NMR experiments in deuterated water. The experimentally-determined Ras-binding site comprises residues belonging to the α-2 helix and the β-3 strand of the central β-sheet in the Switch 2 region. Synthetic molecules bind Ras in a region belonging to the more extended Ras/GEF-binding site, and a possible mechanism of Ras inhibition by these compounds can be the blockade of GEF-mediated nucleotide exchange. ","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"95-116"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/B978-0-12-416749-0.00005-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32513121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

A two-hybrid approach to identify inhibitors of the RAS-RAF interaction. 鉴定RAS-RAF相互作用抑制剂的双杂交方法。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00010-5

Vladimir Khazak, Susanne Eyrisch, Juran Kato, Fuyuhiko Tamanoi, Erica A Golemis

{"title":"A two-hybrid approach to identify inhibitors of the RAS-RAF interaction.","authors":"Vladimir Khazak, Susanne Eyrisch, Juran Kato, Fuyuhiko Tamanoi, Erica A Golemis","doi":"10.1016/B978-0-12-416749-0.00010-5","DOIUrl":"https://doi.org/10.1016/B978-0-12-416749-0.00010-5","url":null,"abstract":"MCP compounds were developed with the idea to inhibit RAS/RAF interaction. They were identified by carrying out high-throughput screens of chemical compounds for their ability to inhibit RAS/RAF interaction in the yeast two-hybrid assay. A number of compounds including MCP1, MCP53, and MCP110 were identified as active compounds. Their inhibition of the RAS signaling was demonstrated by examining RAF and MEK activities, phosphorylation of ERK as well as characterizing their effects on events downstream of RAF. Direct evidence for the inhibition of RAS/RAF interaction was obtained by carrying out co-IP experiments. MCP compounds inhibit proliferation of a wide range of human cancer cell lines. Combination studies with other drugs showed that MCP compounds synergize with MAPK pathway inhibitors as well as with microtubule-targeting chemotherapeutics. In particular, a strong synergy with paclitaxel was observed. Efficacy to inhibit tumor formation was demonstrated using mouse xenograft models. Combination of MCP110 and paclitaxel was particularly effective in inhibiting tumor growth in a mouse xenograft model of colorectal carcinoma. ","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"213-48"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/B978-0-12-416749-0.00010-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32510933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

The Ras superfamily G-proteins. Ras超家族g蛋白。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00001-4

Ashley L Tetlow, Fuyuhiko Tamanoi

引用次数: 13

Aptamer-derived peptide inhibitors of Rho guanine nucleotide exchange factors. 鸟嘌呤核苷酸交换因子的适配体衍生肽抑制剂。

Enzymes Pub Date : 2013-01-01 Epub Date: 2013-08-08 DOI: 10.1016/B978-0-12-416749-0.00007-5

Susanne Schmidt, Anne Debant

{"title":"Aptamer-derived peptide inhibitors of Rho guanine nucleotide exchange factors.","authors":"Susanne Schmidt, Anne Debant","doi":"10.1016/B978-0-12-416749-0.00007-5","DOIUrl":"https://doi.org/10.1016/B978-0-12-416749-0.00007-5","url":null,"abstract":"Small G proteins of the Rho family and their activators the guanine nucleotide exchange factors (RhoGEFs) regulate essential cellular functions and their deregulation has been associated with an amazing variety of human disorders, including cancer, inflammation, vascular diseases, and mental retardation. Rho GTPases and RhoGEFs therefore represent important targets for inhibition, not only in basic research but also for therapeutic purposes, and strategies to inhibit their function are actively being sought. Our lab has been very active in this field and has used the peptide aptamer technology to develop the first RhoGEF inhibitor, using the RhoGEF Trio as a model. Trio function has been described mainly in cell motility and axon growth in the nervous system via Rac1 GTPase activation, but recent findings suggest it to play also a role in the aggressive phenotype of various cancers, making it an attractive target for drug discovery. The object of this chapter is to demonstrate that targeting a RhoGEF using the peptide aptamer technology represents a valid and efficient approach to inhibit cellular processes in which Rho GTPase activity is upregulated. This is illustrated here by the first description of a peptide inhibitor of the oncogenic RhoGEF Tgat, TRIP(E32G), which is functional in vivo. On a long-term perspective, these peptide inhibitors can also serve as therapeutic tools or as guides for the discovery of small-molecule drugs, using an aptamer displacement screen. ","PeriodicalId":39097,"journal":{"name":"Enzymes","volume":" ","pages":"147-68"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/B978-0-12-416749-0.00007-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32513122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3