7OKD

Crystal structure of human BCL6 BTB domain in complex with compound 25

7OKD の概要

• エントリーDOI: 10.2210/pdb7okd/pdb
• 分子名称: B-cell lymphoma 6 protein, 2-chloranyl-4-[[4-[2-(5-cyclopropylpyrimidin-2-yl)propan-2-ylamino]-1-methyl-2-oxidanylidene-quinolin-6-yl]amino]pyridine-3-carbonitrile, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: cancer, lymphoma, inhibitor, transcription
• 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: 17327.39

構造登録者

Gunnell, E.A.,Le Bihan, Y.-V.,van Montfort, R.L.M. (登録日: 2021-05-17, 公開日: 2021-12-08, 最終更新日: 2024-01-31)

主引用文献

Lloyd, M.G.,Huckvale, R.,Cheung, K.J.,Rodrigues, M.J.,Collie, G.W.,Pierrat, O.A.,Gatti Iou, M.,Carter, M.,Davis, O.A.,McAndrew, P.C.,Gunnell, E.,Le Bihan, Y.V.,Talbot, R.,Henley, A.T.,Johnson, L.D.,Hayes, A.,Bright, M.D.,Raynaud, F.I.,Meniconi, M.,Burke, R.,van Montfort, R.L.M.,Rossanese, O.W.,Bellenie, B.R.,Hoelder, S.
Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.
J.Med.Chem., 64:17079-17097, 2021

PubMed Abstract: We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.

PubMed: 34846884
DOI: 10.1021/acs.jmedchem.1c00946

実験手法

X-RAY DIFFRACTION (1.94 Å)