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dc.contributor.authorPierrat, OA
dc.contributor.authorLiu, M
dc.contributor.authorCollie, GW
dc.contributor.authorShetty, K
dc.contributor.authorRodrigues, MJ
dc.contributor.authorLe Bihan, Y-V
dc.contributor.authorGunnell, EA
dc.contributor.authorMcAndrew, PC
dc.contributor.authorStubbs, M
dc.contributor.authorRowlands, MG
dc.contributor.authorYahya, N
dc.contributor.authorShehu, E
dc.contributor.authorTalbot, R
dc.contributor.authorPickard, L
dc.contributor.authorBellenie, BR
dc.contributor.authorCheung, K-MJ
dc.contributor.authorDrouin, L
dc.contributor.authorInnocenti, P
dc.contributor.authorWoodward, H
dc.contributor.authorDavis, OA
dc.contributor.authorLloyd, MG
dc.contributor.authorVarela, A
dc.contributor.authorHuckvale, R
dc.contributor.authorBroccatelli, F
dc.contributor.authorCarter, M
dc.contributor.authorGaliwango, D
dc.contributor.authorHayes, A
dc.contributor.authorRaynaud, FI
dc.contributor.authorBryant, C
dc.contributor.authorWhittaker, S
dc.contributor.authorRossanese, OW
dc.contributor.authorHoelder, S
dc.contributor.authorBurke, R
dc.contributor.authorvan Montfort, RLM
dc.coverage.spatialEngland
dc.date.accessioned2022-11-15T15:07:04Z
dc.date.available2022-11-15T15:07:04Z
dc.date.issued2022-11-03
dc.identifier18633
dc.identifier10.1038/s41598-022-23264-z
dc.identifier.citationScientific Reports, 2022, 12 (1), pp. 18633 -
dc.identifier.issn2045-2322
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5557
dc.identifier.eissn2045-2322
dc.identifier.eissn2045-2322
dc.identifier.doi10.1038/s41598-022-23264-z
dc.description.abstractBy suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.
dc.formatElectronic
dc.format.extent18633 -
dc.languageeng
dc.language.isoeng
dc.publisherNATURE PORTFOLIO
dc.relation.ispartofScientific Reports
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectCrystallography, X-Ray
dc.subjectProto-Oncogene Proteins c-bcl-6
dc.subjectLymphoma, Large B-Cell, Diffuse
dc.subjectDrug Design
dc.subjectLigands
dc.titleDiscovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.
dc.typeJournal Article
dcterms.dateAccepted2022-10-27
dc.date.updated2022-11-15T10:06:26Z
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41598-022-23264-z
rioxxterms.licenseref.startdate2022-11-03
rioxxterms.typeJournal Article/Review
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/36329085
pubs.issue1
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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublished online
pubs.publisher-urlhttp://dx.doi.org/10.1038/s41598-022-23264-z
pubs.volume12
icr.researchteamHit Discov Struct Design
dc.contributor.icrauthorPierrat, Olivier
dc.contributor.icrauthorTalbot, Rachel
dc.contributor.icrauthorRaynaud, Florence
dc.contributor.icrauthorRossanese, Olivia
dc.contributor.icrauthorHoelder, Swen
dc.contributor.icrauthorBurke, Rosemary
dc.contributor.icrauthorVan Montfort, Robert
icr.provenanceDeposited by Dr Rosemary Burke on 2022-11-15. Deposit type is initial. No. of files: 1. Files: Discovering cell-active BCL6 inhibitors effectively combining biochemical HTS with multiple biophysical techniques, X-ray cr.pdf


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/