6TOK
Crystal structure of human BCL6 BTB domain in complex with compound 23d
Summary for 6TOK
| Entry DOI | 10.2210/pdb6tok/pdb |
| Descriptor | B-cell lymphoma 6 protein, ALA-TRP-VAL-ILE-PRO-ALA, 5-[[5-chloranyl-2-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]amino]-1-methyl-3-(3-methyl-3-oxidanyl-butyl)benzimidazol-2-one, ... (6 entities in total) |
| Functional Keywords | cancer, lymphoma, inhibitor, degrader, transcription |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 16705.99 |
| 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 Cited by 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: 32275432DOI: 10.1021/acs.jmedchem.9b02076 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.43 Å) |
Structure validation
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