{"id":13459,"date":"2018-05-18T12:22:00","date_gmt":"2018-05-18T12:22:00","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/?post_type=journal-paper&#038;p=13459"},"modified":"2026-01-30T12:32:00","modified_gmt":"2026-01-30T12:32:00","slug":"fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-that-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2-2","status":"publish","type":"journal-paper","link":"https:\/\/www.sygnaturediscovery.com\/fr\/journal-paper\/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-that-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2-2\/","title":{"rendered":"Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1\/2"},"content":{"rendered":"\n<p>Tom D. Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko M. Buck, Megan Cassidy, Juan Castro, Aur\u00e9lie Courtin, James E. H. Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M. Griffiths-Jones, John F. Lyons, Vanessa Martins, Sandra Muench, Joanne M. Munck, David Norton, Marc O\u2019Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C. Rees, Sharna J. Rich, Caroline Richardson, Harpreet Saini, Neil T. Thompson, Nicola G. Wallis, Hugh Walton, Nicola E. Wilsher, Alison J.-A. Woolford, <strong>Michael Cooke<\/strong>, <strong>David Cousin<\/strong>, <strong>Stuart Onions<\/strong>, <strong>Jonathan Shannon<\/strong>, <strong>John Watts<\/strong>, Christopher W. Murray<\/p>\n\n\n\n<p><strong>Abstract<\/strong><\/p>\n\n\n\n<p>Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1\/2. Here, we describe the fragment-based generation of ERK1\/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1\/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-\u03b1 helix afforded highly potent ERK1\/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1\/2 modulating ERK1\/2 inhibitors.<\/p>\n\n\n\n<p>Ref:<a href=\"https:\/\/pubs.acs.org\/doi\/10.1021\/acs.jmedchem.8b00421\"> J Med Chem 2018<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"featured_media":0,"template":"","category":[682,713],"resource_tag":[],"class_list":["post-13459","journal-paper","type-journal-paper","status-publish","hentry","category-chemistry","category-medicinal-chemistry"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.4 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1\/2 - Sygnature<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.sygnaturediscovery.com\/fr\/journal-paper\/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-that-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2-2\/\" \/>\n<meta property=\"og:locale\" content=\"fr_CA\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1\/2 - 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