dc.contributor.author | Harnden, AC | |
dc.contributor.author | Davis, OA | |
dc.contributor.author | Box, GM | |
dc.contributor.author | Hayes, A | |
dc.contributor.author | Johnson, LD | |
dc.contributor.author | Henley, AT | |
dc.contributor.author | de Haven Brandon, AK | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | Cheung, K-MJ | |
dc.contributor.author | Brennan, A | |
dc.contributor.author | Huckvale, R | |
dc.contributor.author | Pierrat, OA | |
dc.contributor.author | Talbot, R | |
dc.contributor.author | Bright, MD | |
dc.contributor.author | Akpinar, HA | |
dc.contributor.author | Miller, DSJ | |
dc.contributor.author | Tarantino, D | |
dc.contributor.author | Gowan, S | |
dc.contributor.author | de Klerk, S | |
dc.contributor.author | McAndrew, PC | |
dc.contributor.author | Le Bihan, Y-V | |
dc.contributor.author | Meniconi, M | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Kirkin, V | |
dc.contributor.author | van Montfort, RLM | |
dc.contributor.author | Raynaud, FI | |
dc.contributor.author | Rossanese, OW | |
dc.contributor.author | Bellenie, BR | |
dc.contributor.author | Hoelder, S | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-08-04T13:22:18Z | |
dc.date.available | 2023-08-04T13:22:18Z | |
dc.date.issued | 2023-04-27 | |
dc.identifier.citation | Journal of Medicinal Chemistry, 2023, 66 (8), pp. 5892 - 5906 | en_US |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5923 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.3c00155 | |
dc.description.abstract | B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing. | |
dc.format | Print-Electronic | |
dc.format.extent | 5892 - 5906 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | AMER CHEMICAL SOC | en_US |
dc.relation.ispartof | Journal of Medicinal Chemistry | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Animals | |
dc.subject | Proto-Oncogene Proteins c-bcl-6 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Quinolones | |
dc.subject | Transcription Factors | |
dc.subject | Lymphoma, Large B-Cell, Diffuse | |
dc.subject | Disease Models, Animal | |
dc.title | Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-04-27 | |
dc.date.updated | 2023-08-04T13:20:23Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.3c00155 | en_US |
rioxxterms.licenseref.startdate | 2023-04-27 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37026591 | |
pubs.issue | 8 | |
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-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1021/acs.jmedchem.3c00155 | |
pubs.volume | 66 | |
icr.researchteam | Hit Discov Struct Design | en_US |
icr.researchteam | Clinical Pharma & Trials | en_US |
icr.researchteam | Medicinal Chemistry 4 | en_US |
dc.contributor.icrauthor | Pierrat, Olivier | |
dc.contributor.icrauthor | Talbot, Rachel | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Van Montfort, Robert | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Hoelder, Swen | |
icr.provenance | Deposited by Mr Arek Surman on 2023-08-04. Deposit type is initial. No. of files: 1. Files: Discovery of an iIn Vivoi Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.pdf | |