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dc.contributor.authorQuevedo, CE
dc.contributor.authorCruz-Migoni, A
dc.contributor.authorBery, N
dc.contributor.authorMiller, A
dc.contributor.authorTanaka, T
dc.contributor.authorPetch, D
dc.contributor.authorBataille, CJR
dc.contributor.authorLee, LYW
dc.contributor.authorFallon, PS
dc.contributor.authorTulmin, H
dc.contributor.authorEhebauer, MT
dc.contributor.authorFernandez-Fuentes, N
dc.contributor.authorRussell, AJ
dc.contributor.authorCarr, SB
dc.contributor.authorPhillips, SEV
dc.contributor.authorRabbitts, TH
dc.date.accessioned2020-12-21T11:36:54Z
dc.date.issued2018-08-09
dc.identifier.citationNature communications, 2018, 9 (1), pp. 3169 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4259
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-018-05707-2
dc.description.abstractTargeting specific protein-protein interactions (PPIs) is an attractive concept for drug development, but hard to implement since intracellular antibodies do not penetrate cells and most small-molecule drugs are considered unsuitable for PPI inhibition. A potential solution to these problems is to select intracellular antibody fragments to block PPIs, use these antibody fragments for target validation in disease models and finally derive small molecules overlapping the antibody-binding site. Here, we explore this strategy using an anti-mutant RAS antibody fragment as a competitor in a small-molecule library screen for identifying RAS-binding compounds. The initial hits are optimized by structure-based design, resulting in potent RAS-binding compounds that interact with RAS inside the cells, prevent RAS-effector interactions and inhibit endogenous RAS-dependent signalling. Our results may aid RAS-dependent cancer drug development and demonstrate a general concept for developing small compounds to replace intracellular antibody fragments, enabling rational drug development to target validated PPIs.
dc.formatElectronic
dc.format.extent3169 - ?
dc.languageeng
dc.language.isoeng
dc.publisherNATURE PORTFOLIO
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectras Proteins
dc.subjectImmunoglobulin Fragments
dc.subjectRecombinant Proteins
dc.subjectAntibodies
dc.subjectBinding Sites, Antibody
dc.subjectCrystallography, X-Ray
dc.subjectSurface Plasmon Resonance
dc.subjectSignal Transduction
dc.subjectCell Survival
dc.subjectProtein Binding
dc.subjectMutation
dc.subjectSmall Molecule Libraries
dc.subjectHEK293 Cells
dc.subjectBiomarkers
dc.subjectProtein Domains
dc.titleSmall molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment.
dc.typeJournal Article
dcterms.dateAccepted2018-07-18
rioxxterms.versionofrecord10.1038/s41467-018-05707-2
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-08-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
pubs.issue1
pubs.notesNot known
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/Chromosomal Translocations and Intracellular Antibody Therapeutics
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/Chromosomal Translocations and Intracellular Antibody Therapeutics
pubs.publication-statusPublished
pubs.volume9
pubs.embargo.termsNot known
icr.researchteamChromosomal Translocations and Intracellular Antibody Therapeutics
dc.contributor.icrauthorRabbitts, Terence


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