6TOO

Crystal structure of human BCL6 BTB domain in complex with compound 11a

6TOO の概要

• エントリーDOI: 10.2210/pdb6too/pdb
• 分子名称: B-cell lymphoma 6 protein, ALA-TRP-VAL-ILE-PRO-ALA, 2-chloranyl-4-[[1-methyl-3-[(2~{S})-2-oxidanylbutyl]-2-oxidanylidene-benzimidazol-5-yl]amino]pyridine-3-carbonitrile, ... (5 entities in total)
• 機能のキーワード: cancer, lymphoma, inhibitor, degrader, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 15750.72

構造登録者

Collie, G.W.,Rodrigues, M.J.,Le Bihan, Y.-V.,van Montfort, R.L.M. (登録日: 2019-12-11, 公開日: 2020-04-22, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.53 Å)