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dc.contributor.authorTanaka, T
dc.contributor.authorThomas, J
dc.contributor.authorVan Montfort, R
dc.contributor.authorMiller, A
dc.contributor.authorRabbitts, T
dc.date.accessioned2021-01-20T15:46:53Z
dc.date.issued2021-12
dc.identifier1712
dc.identifier.citationScientific Reports, 2021, 11 (1)
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4298
dc.identifier.eissn2045-2322
dc.identifier.doi10.1038/s41598-021-81262-z
dc.description.abstractAbstract Intracellular antibodies are valuable tools for target validation studies for clinical situations such as cancer. Recently we have shown that antibodies can be used for drug discovery in screening for chemical compounds surrogates by showing that compounds could be developed to the so-called undruggable RAS protein family. This method, called A nti b ody- d erived compound ( Abd ) technology, employed intracellular antibodies binding to RAS in a competitive surface plasmon resonance chemical library screen. Success with this method requires a high affinity interaction between the antibody and the target. We now show that reduction in the affinity (dematuration) of the anti-active RAS antibody facilitates the screening of a chemical library using an in vitro AlphaScreen method. This identified active RAS specific-binding Abd compounds that inhibit the RAS-antibody interaction. One compound is shown to be a pan-RAS binder to KRAS, HRAS and NRAS-GTP proteins with a Kd of average 37 mM, offering the possibility of a new chemical series that interacts with RAS in the switch region where the intracellular antibody binds. This simple approach shows the druggability of RAS and is generally applicable to antibody-derived chemical library screening by affording flexibility through simple antibody affinity variation. This approach can be applied to find Abd compounds as surrogates of antibody-combining sites for novel drug development in a range of human diseases.
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titlePan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody
dc.typeJournal Article
rioxxterms.versionofrecord10.1038/s41598-021-81262-z
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-12
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScientific Reports
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 online
pubs.volume11
pubs.embargo.termsNot known
icr.researchteamChromosomal Translocations and Intracellular Antibody Therapeuticsen_US
dc.contributor.icrauthorRabbitts, Terenceen


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