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Achieving <i>In Vivo</i> Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

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.

SUBMITTER: Bellenie BR 

PROVIDER: S-EPMC7184563 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Achieving &lt;i&gt;In Vivo&lt;/i&gt; Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

Bellenie Benjamin R BR   Cheung Kwai-Ming J KJ   Varela Ana A   Pierrat Olivier A OA   Collie Gavin W GW   Box Gary M GM   Bright Michael D MD   Gowan Sharon S   Hayes Angela A   Rodrigues Matthew J MJ   Shetty Kartika N KN   Carter Michael M   Davis Owen A OA   Henley Alan T AT   Innocenti Paolo P   Johnson Louise D LD   Liu Manjuan M   de Klerk Selby S   Le Bihan Yann-Vaï YV   Lloyd Matthew G MG   McAndrew P Craig PC   Shehu Erald E   Talbot Rachel R   Woodward Hannah L HL   Burke Rosemary R   Kirkin Vladimir V   van Montfort Rob L M RLM   Raynaud Florence I FI   Rossanese Olivia W OW   Hoelder Swen S  

Journal of medicinal chemistry 20200410 8

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 disc  ...[more]