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dc.contributor.authorDavis, OA
dc.contributor.authorCheung, K-MJ
dc.contributor.authorBrennan, A
dc.contributor.authorLloyd, MG
dc.contributor.authorRodrigues, MJ
dc.contributor.authorPierrat, OA
dc.contributor.authorCollie, GW
dc.contributor.authorLe Bihan, Y-V
dc.contributor.authorHuckvale, R
dc.contributor.authorHarnden, AC
dc.contributor.authorVarela, A
dc.contributor.authorBright, MD
dc.contributor.authorEve, P
dc.contributor.authorHayes, A
dc.contributor.authorHenley, AT
dc.contributor.authorCarter, MD
dc.contributor.authorMcAndrew, PC
dc.contributor.authorTalbot, R
dc.contributor.authorBurke, R
dc.contributor.authorvan Montfort, RLM
dc.contributor.authorRaynaud, FI
dc.contributor.authorRossanese, OW
dc.contributor.authorMeniconi, M
dc.contributor.authorBellenie, BR
dc.contributor.authorHoelder, S
dc.coverage.spatialUnited States
dc.date.accessioned2022-08-23T11:31:26Z
dc.date.available2022-08-23T11:31:26Z
dc.date.issued2022-06-23
dc.identifier.citationJournal of Medicinal Chemistry, 2022, 65 (12), pp. 8169 - 8190
dc.identifier.issn0022-2623
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5313
dc.identifier.eissn1520-4804
dc.identifier.eissn1520-4804
dc.identifier.doi10.1021/acs.jmedchem.1c02174
dc.description.abstractTo identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.
dc.formatPrint-Electronic
dc.format.extent8169 - 8190
dc.languageeng
dc.language.isoeng
dc.publisherAMER CHEMICAL SOC
dc.relation.ispartofJournal of Medicinal Chemistry
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBTB-POZ Domain
dc.subjectProtein Binding
dc.subjectProto-Oncogene Proteins c-bcl-6
dc.titleOptimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
dc.typeJournal Article
dcterms.dateAccepted2021-12-01
dc.date.updated2022-08-23T11:30:23Z
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/acs.jmedchem.1c02174
rioxxterms.licenseref.startdate2022-06-23
rioxxterms.typeJournal Article/Review
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/35657291
pubs.issue12
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/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry)
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
pubs.volume65
icr.researchteamHit Discov Struct Design
icr.researchteamClinical Pharma & Trials
icr.researchteamDirectorate Canc Ther
icr.researchteamMedicinal Chemistry 4
dc.contributor.icrauthorPierrat, Olivier
dc.contributor.icrauthorTalbot, Rachel
dc.contributor.icrauthorBurke, Rosemary
dc.contributor.icrauthorVan Montfort, Robert
dc.contributor.icrauthorRaynaud, Florence
dc.contributor.icrauthorRossanese, Olivia
dc.contributor.icrauthorHoelder, Swen
icr.provenanceDeposited by Mr Arek Surman on 2022-08-23. Deposit type is initial. No. of files: 1. Files: Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.pdf


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