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.

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