@article{discovery10096411, journal = {Journal of Medicinal Chemistry}, pages = {4047--4068}, month = {April}, note = {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.}, title = {Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders}, number = {8}, volume = {63}, year = {2020}, keywords = {Mixtures, Degradation, Assays, Solubility, Molecules}, author = {Bellenie, BR and Cheung, K-MJ and Varela, A and Pierrat, OA and Collie, GW and Box, GM and Bright, MD and Gowan, S and Hayes, A and Rodrigues, MJ and Shetty, KN and Carter, M and Davis, OA and Henley, AT and Innocenti, P and Johnson, LD and Liu, M and De Klerk, S and Le Bihan, Y-V and Lloyd, MG and McAndrew, PC and Shehu, E and Talbot, R and Woodward, HL and Burke, R and Kirkin, V and Van Montfort, RLM and Raynaud, FI and Rossanese, OW and Hoelder, S}, url = {https://doi.org/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.} }