6TOM

Crystal structure of human BCL6 BTB domain in complex with compound 1

Summary for 6TOM

• Entry DOI: 10.2210/pdb6tom/pdb
• Descriptor: B-cell lymphoma 6 protein, 5-[[2-[(3~{S},5~{R})-4,4-bis(fluoranyl)-3,5-dimethyl-piperidin-1-yl]-5-chloranyl-pyrimidin-4-yl]amino]-1-methyl-3-(3-methyl-3-oxidanyl-butyl)benzimidazol-2-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: cancer, lymphoma, inhibitor, degrader, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 17194.15

Authors

Rodrigues, M.J.,Le Bihan, Y.-V.,van Montfort, R.L.M. (deposition date: 2019-12-11, release date: 2020-04-22, Last modification date: 2024-01-24)

Primary citation

Bellenie, B.R.,Cheung, K.J.,Varela, A.,Pierrat, O.A.,Collie, G.W.,Box, G.M.,Bright, M.D.,Gowan, S.,Hayes, A.,Rodrigues, M.J.,Shetty, K.N.,Carter, M.,Davis, O.A.,Henley, A.T.,Innocenti, P.,Johnson, L.D.,Liu, M.,de Klerk, S.,Le Bihan, Y.V.,Lloyd, M.G.,McAndrew, P.C.,Shehu, E.,Talbot, R.,Woodward, H.L.,Burke, R.,Kirkin, V.,van Montfort, R.L.M.,Raynaud, F.I.,Rossanese, O.W.,Hoelder, S.
AchievingIn VivoTarget Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.
J.Med.Chem., 63:4047-4068, 2020

PubMed 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-((3,5)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2-benzo[]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

PubMed: 32275432
DOI: 10.1021/acs.jmedchem.9b02076

Experimental method

X-RAY DIFFRACTION (1.9 Å)