{"id":13441,"date":"2017-09-11T17:34:52","date_gmt":"2017-09-11T21:34:52","guid":{"rendered":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/?p=13441"},"modified":"2026-01-07T15:14:44","modified_gmt":"2026-01-07T20:14:44","slug":"giv-is-druggable","status":"publish","type":"post","link":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/2017\/09\/11\/giv-is-druggable\/","title":{"rendered":"GIV is Druggable"},"content":{"rendered":"<p class=\"p1\">Earlier this year, the <a href=\"https:\/\/www.bumc.bu.edu\/biochemcellbio\/profiles\/mikel-garcia-marcos\/\">Garcia-Marcos <\/a>laboratory reported detailed structural information describing how trimeric G proteins are activated by GBA motifs, protein segments capable of triggering G-protein signaling by a GPCR-independent mechanism. The work focused on GIV, a nucleotide exchange factor for G\u03b1i3. Because we had previously shown that the GIV-G\u03b1i3 interaction is required for cancer metastasis, we investigated if it could be disrupted by small molecules. The identification of such compounds would represent the first step in the development of novel anti-metastatic drugs, an urgently needed arm of current cancer therapeutic strategies.<\/p>\n<p class=\"p1\">Disrupting protein-protein interactions (PPIs) like the one established by GIV and G\u03b1i3, however, is notoriously challenging. A significant hurdle to therapeutic development is demonstrating that a given PPI can be targeted by small molecules in the first place \u2013 i.e. they tend not to be \u201cdruggable.\u201d To establish the druggability of our target, we combined computational approaches and wet laboratory techniques, drawing on insights gathered from our recent studies. We concluded disruption of the PPI target could indeed be achieved by small molecules and furthermore that the mode of action can be readily predicted by utilizing structural information.<a href=\"https:\/\/www.bumc.bu.edu\/biochemcellbio\/nf023-pose-fullprotein\/\" rel=\"attachment wp-att-13446\"><img loading=\"lazy\" src=\"\/biochemcellbio\/files\/2017\/09\/NF023-Pose-FullProtein-356x300.png\" alt=\"NF023 Pose FullProtein\" width=\"356\" height=\"300\" class=\"alignright size-medium wp-image-13446\" srcset=\"https:\/\/www.bumc.bu.edu\/biochemcellbio\/files\/2017\/09\/NF023-Pose-FullProtein-356x300.png 356w, https:\/\/www.bumc.bu.edu\/biochemcellbio\/files\/2017\/09\/NF023-Pose-FullProtein-768x647.png 768w, https:\/\/www.bumc.bu.edu\/biochemcellbio\/files\/2017\/09\/NF023-Pose-FullProtein-1024x863.png 1024w, https:\/\/www.bumc.bu.edu\/biochemcellbio\/files\/2017\/09\/NF023-Pose-FullProtein.png 1089w\" sizes=\"(max-width: 356px) 100vw, 356px\" \/><\/a><\/p>\n<p class=\"p1\">\u00a0The work establishes a robust pipeline for the discovery and validation of inhibitors of the GIV-G\u03b1i3 interface and identifies a small molecule that can serve in such a role. A limitation is that the small molecule we validated was not suitable for experimentation in cancer cells or patients. The study nonetheless provides an important proof of principle for the druggability of our target, success with which could be achieved by screening larger libraries of chemical compounds. Such high-throughput screens are currently underway in our laboratory.<\/p>\n<p class=\"p1\">\u00a0This work involved collaboration with the group of Francisco J. Blanco, from the CIC-BioGUNE in Spain and was published in the journal\u00a0<i>Scientific Reports<\/i>.<\/p>\n<p class=\"p2\"><b>\u00a0<\/b><b>Reference<\/b><\/p>\n<p class=\"p2\">The G\u03b1i-GIV binding interface is a druggable protein-protein interaction. DiGiacomo V, de Opakua AI, Papakonstantinou MP, Nguyen LT, Merino N, Blanco-Canosa JB, Blanco FJ, Garcia-Marcos M.\u00a0<b>Sci Rep<\/b>. 2017 Aug 17;7(1):8575. doi: 10.1038\/s41598-017-08829-7. PMID: 28819150<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Earlier this year, the Garcia-Marcos laboratory reported detailed structural information describing how trimeric G proteins are activated by GBA motifs, [&hellip;]<\/p>\n","protected":false},"author":1191,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[104,4654,100],"tags":[],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/posts\/13441"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/users\/1191"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/comments?post=13441"}],"version-history":[{"count":3,"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/posts\/13441\/revisions"}],"predecessor-version":[{"id":13447,"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/posts\/13441\/revisions\/13447"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/media?parent=13441"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/categories?post=13441"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/biochemcellbio\/wp-json\/wp\/v2\/tags?post=13441"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}