Details

Autor(en) / Beteiligte

• Bellenie, Benjamin R
• Cheung, Kwai-Ming J
• Varela, Ana
• Pierrat, Olivier A
• Collie, Gavin W
• Box, Gary M
• Bright, Michael D
• Gowan, Sharon
• Hayes, Angela
• Rodrigues, Matthew J
• Shetty, Kartika N
• Carter, Michael
• Davis, Owen A
• Henley, Alan T
• Innocenti, Paolo
• Johnson, Louise D
• Liu, Manjuan
• de Klerk, Selby
• Le Bihan, Yann-Vaï
• Lloyd, Matthew G
• McAndrew, P. Craig
• Shehu, Erald
• Talbot, Rachel
• Woodward, Hannah L
• Burke, Rosemary
• Kirkin, Vladimir
• van Montfort, Rob L. M
• Raynaud, Florence I
• Rossanese, Olivia W
• Hoelder, Swen

Titel

Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders

Ist Teil von

• Journal of medicinal chemistry, 2020-04, Vol.63 (8), p.4047-4068

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.