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Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.

dc.contributor.authorHuckvale, R
dc.contributor.authorHarnden, AC
dc.contributor.authorCheung, K-MJ
dc.contributor.authorPierrat, OA
dc.contributor.authorTalbot, R
dc.contributor.authorBox, GM
dc.contributor.authorHenley, AT
dc.contributor.authorde Haven Brandon, AK
dc.contributor.authorHallsworth, AE
dc.contributor.authorBright, MD
dc.contributor.authorAkpinar, HA
dc.contributor.authorMiller, DSJ
dc.contributor.authorTarantino, D
dc.contributor.authorGowan, S
dc.contributor.authorHayes, A
dc.contributor.authorGunnell, EA
dc.contributor.authorBrennan, A
dc.contributor.authorDavis, OA
dc.contributor.authorJohnson, LD
dc.contributor.authorde Klerk, S
dc.contributor.authorMcAndrew, C
dc.contributor.authorLe Bihan, Y-V
dc.contributor.authorMeniconi, M
dc.contributor.authorBurke, R
dc.contributor.authorKirkin, V
dc.contributor.authorvan Montfort, RLM
dc.contributor.authorRaynaud, FI
dc.contributor.authorRossanese, OW
dc.contributor.authorBellenie, BR
dc.contributor.authorHoelder, S
dc.coverage.spatialUnited States
dc.date.accessioned2022-08-23T10:59:32Z
dc.date.available2022-08-23T10:59:32Z
dc.date.issued2022-06-23
dc.identifier.citationJournal of Medicinal Chemistry, 2022, 65 (12), pp. 8191 - 8207
dc.identifier.issn0022-2623
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5312
dc.identifier.eissn1520-4804
dc.identifier.eissn1520-4804
dc.identifier.doi10.1021/acs.jmedchem.1c02175
dc.description.abstractThe transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.
dc.formatPrint-Electronic
dc.format.extent8191 - 8207
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.subjectAnimals
dc.subjectCarcinogenesis
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectHumans
dc.subjectMice
dc.subjectProto-Oncogene Proteins c-bcl-6
dc.titleImproved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.
dc.typeJournal Article
dcterms.dateAccepted2022-06-03
dc.date.updated2022-08-23T10:58:27Z
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/acs.jmedchem.1c02175
rioxxterms.licenseref.startdate2022-06-23
rioxxterms.typeJournal Article/Review
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/35653645
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.icrauthorGowan, Sharon
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: Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 iIn Vivoi.pdf


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