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dc.contributor.authorAbbott, JRen_US
dc.contributor.authorPatel, PAen_US
dc.contributor.authorHowes, JEen_US
dc.contributor.authorAkan, DTen_US
dc.contributor.authorKennedy, JPen_US
dc.contributor.authorBurns, MCen_US
dc.contributor.authorBrowning, CFen_US
dc.contributor.authorSun, Qen_US
dc.contributor.authorRossanese, OWen_US
dc.contributor.authorPhan, Jen_US
dc.contributor.authorWaterson, AGen_US
dc.contributor.authorFesik, SWen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2018-11-14T09:25:46Z
dc.date.issued2018-09-13en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30258545en_US
dc.identifier.citationACS Med Chem Lett, 2018, 9 (9), pp. 941 - 946en_US
dc.identifier.issn1948-5875en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2926
dc.identifier.doi10.1021/acsmedchemlett.8b00296en_US
dc.description.abstractProteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.en_US
dc.format.extent941 - 946en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleDiscovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-08-08en_US
rioxxterms.versionofrecord10.1021/acsmedchemlett.8b00296en_US
rioxxterms.licenseref.startdate2018-09-13en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfACS Med Chem Letten_US
pubs.issue9en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.publication-statusPublished onlineen_US
pubs.volume9en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTarget Evaluation and Molecular Therapeuticsen_US
dc.contributor.icrauthorRossanese, Oliviaen_US


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