Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.
Benjamin R BellenieKwai-Ming J CheungAna VarelaOlivier A PierratGavin W CollieGary M BoxMichael D BrightSharon GowanAngela HayesMatthew J RodriguesKartika N ShettyMichael CarterOwen A DavisAlan T HenleyPaolo InnocentiLouise D JohnsonManjuan LiuSelby de KlerkYann-Vaï Le BihanMatthew G LloydP Craig McAndrewErald ShehuRachel TalbotHannah L WoodwardRosemary BurkeVladimir KirkinRob L M van MontfortFlorence I RaynaudOlivia W RossaneseSwen HoelderPublished in: Journal of medicinal chemistry (2020)
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.