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

Bellenie, BR; Cheung, K-MJ; Varela, A; Pierrat, OA; Collie, GW; Box, GM; Bright, MD; ... Hoelder, S; + view all (2020) Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. Journal of Medicinal Chemistry , 63 (8) pp. 4047-4068. 10.1021/acs.jmedchem.9b02076. Green open access

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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.

Type: Article
Title: Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jmedchem.9b02076
Publisher version: https://doi.org/10.1021/acs.jmedchem.9b02076
Language: English
Additional information: This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html), which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Keywords: Mixtures, Degradation, Assays, Solubility, Molecules
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10096411
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