5W0E

CREBBP bromodomain in complex with Cpd19 (3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide)

5W0E の概要

• エントリーDOI: 10.2210/pdb5w0e/pdb
• 関連するPDBエントリー: 5VZS
• 分子名称: CREB-binding protein, 3-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-N-methyl-1-(oxan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (3 entities in total)
• 機能のキーワード: crebbp, bromodomain, small molecule inhibitor, transcription regulator-inhibitor complex, transcription regulator/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q92793
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18155.57

構造登録者

Murray, J.M. (登録日: 2017-05-30, 公開日: 2018-02-21, 最終更新日: 2023-10-04)

主引用文献

Bronner, S.M.,Murray, J.,Romero, F.A.,Lai, K.W.,Tsui, V.,Cyr, P.,Beresini, M.H.,de Leon Boenig, G.,Chen, Z.,Choo, E.F.,Clark, K.R.,Crawford, T.D.,Jayaram, H.,Kaufman, S.,Li, R.,Li, Y.,Liao, J.,Liang, X.,Liu, W.,Ly, J.,Maher, J.,Wai, J.,Wang, F.,Zheng, A.,Zhu, X.,Magnuson, S.
A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors.
J. Med. Chem., 60:10151-10171, 2017

PubMed Abstract: The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To demonstrate the utility of our hybridization approach, two analogues containing unique Asn binders and the optimized tetrahydroquinoline moiety were rapidly optimized to yield single-digit nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1) and the broader bromodomain family.

PubMed: 29155580
DOI: 10.1021/acs.jmedchem.7b01372

実験手法

X-RAY DIFFRACTION (1.41 Å)