2. Academic Validation
  3. Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders

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

  • J Med Chem. 2020 Apr 23;63(8):4047-4068. doi: 10.1021/acs.jmedchem.9b02076.
Benjamin R Bellenie,  Kwai-Ming J Cheung,  Ana Varela,  Olivier A Pierrat,  Gavin W Collie,  Gary M Box,  Michael D Bright,  Sharon Gowan,  Angela Hayes,  Matthew J Rodrigues,  Kartika N Shetty,  Michael Carter,  Owen A Davis,  Alan T Henley,  Paolo Innocenti,  Louise D Johnson,  Manjuan Liu,  Selby de Klerk,  Yann-Vaï Le Bihan,  Matthew G Lloyd,  P Craig McAndrew,  Erald Shehu,  Rachel Talbot,  Hannah L Woodward,  Rosemary Burke,  Vladimir Kirkin,  Rob L M van Montfort,  Florence I Raynaud,  Olivia W Rossanese,  Swen Hoelder
PMID: 32275432 DOI: 10.1021/acs.jmedchem.9b02076
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z