7Q7V

Crystal structure of human BCL6 BTB domain in complex with compound 12a

7Q7V の概要

• エントリーDOI: 10.2210/pdb7q7v/pdb
• 分子名称: B-cell lymphoma 6 protein, 2-chloranyl-4-[[(2R)-2-cyclopropyl-7-methyl-6-oxidanylidene-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl]amino]pyridine-3-carbonitrile, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: transcription, inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17123.10

構造登録者

Rodrigues, M.J.,Le Bihan, Y.-V.,van Montfort, R.L.M. (登録日: 2021-11-09, 公開日: 2022-06-15, 最終更新日: 2024-01-31)

主引用文献

Davis, O.A.,Cheung, K.J.,Brennan, A.,Lloyd, M.G.,Rodrigues, M.J.,Pierrat, O.A.,Collie, G.W.,Le Bihan, Y.V.,Huckvale, R.,Harnden, A.C.,Varela, A.,Bright, M.D.,Eve, P.,Hayes, A.,Henley, A.T.,Carter, M.D.,McAndrew, P.C.,Talbot, R.,Burke, R.,van Montfort, R.L.M.,Raynaud, F.I.,Rossanese, O.W.,Meniconi, M.,Bellenie, B.R.,Hoelder, S.
Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
J.Med.Chem., 65:8169-8190, 2022

PubMed Abstract: To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.

PubMed: 35657291
DOI: 10.1021/acs.jmedchem.1c02174

実験手法

X-RAY DIFFRACTION (1.81 Å)