dc.contributor.author | Bellenie, BR | |
dc.contributor.author | Cheung, K-MJ | |
dc.contributor.author | Varela, A | |
dc.contributor.author | Pierrat, OA | |
dc.contributor.author | Collie, GW | |
dc.contributor.author | Box, GM | |
dc.contributor.author | Bright, MD | |
dc.contributor.author | Gowan, S | |
dc.contributor.author | Hayes, A | |
dc.contributor.author | Rodrigues, MJ | |
dc.contributor.author | Shetty, KN | |
dc.contributor.author | Carter, M | |
dc.contributor.author | Davis, OA | |
dc.contributor.author | Henley, AT | |
dc.contributor.author | Innocenti, P | |
dc.contributor.author | Johnson, LD | |
dc.contributor.author | Liu, M | |
dc.contributor.author | de Klerk, S | |
dc.contributor.author | Le Bihan, Y-V | |
dc.contributor.author | Lloyd, MG | |
dc.contributor.author | McAndrew, PC | |
dc.contributor.author | Shehu, E | |
dc.contributor.author | Talbot, R | |
dc.contributor.author | Woodward, HL | |
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 | Hoelder, S | |
dc.date.accessioned | 2020-05-26T12:55:05Z | |
dc.date.issued | 2020-04-23 | |
dc.identifier.citation | Journal of medicinal chemistry, 2020, 63 (8), pp. 4047 - 4068 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3637 | |
dc.identifier.eissn | 1520-4804 | |
dc.identifier.doi | 10.1021/acs.jmedchem.9b02076 | |
dc.description.abstract | Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing. | |
dc.format | Print-Electronic | |
dc.format.extent | 4047 - 4068 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Microsomes, Liver | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, SCID | |
dc.subject | Rats | |
dc.subject | Rats, Sprague-Dawley | |
dc.subject | Benzimidazoles | |
dc.subject | Drug Delivery Systems | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Protein Structure, Tertiary | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Proto-Oncogene Proteins c-bcl-6 | |
dc.subject | Drug Discovery | |
dc.title | Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1021/acs.jmedchem.9b02076 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by-nc/4.0 | |
rioxxterms.licenseref.startdate | 2020-04-10 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of medicinal chemistry | |
pubs.issue | 8 | |
pubs.notes | Not 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/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
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.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/Cancer Pharmacology & Stress Response (CPSR) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Pharmacology & Stress Response (CPSR) | |
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.volume | 63 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Pharmacology & Stress Response (CPSR) | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 4 (including Analytical Chemistry) | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Pierrat, Olivier | |
dc.contributor.icrauthor | Gowan, Sharon | |
dc.contributor.icrauthor | Le Bihan, Yann-Vai | |
dc.contributor.icrauthor | Talbot, Rachel | |
dc.contributor.icrauthor | Burke, Rosemary | |
dc.contributor.icrauthor | Kirkin, Vladimir | |
dc.contributor.icrauthor | Van Montfort, Robert | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Rossanese, Olivia | |
dc.contributor.icrauthor | Hoelder, Swen | |