5KTW

CREBBP bromodomain in complex with Cpd 44 (3-((5-acetyl-1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-isopropylbenzamide)

5KTW の概要

• エントリーDOI: 10.2210/pdb5ktw/pdb
• 関連するPDBエントリー: 5KTX 5KU3
• 分子名称: CREB-binding protein, 3-[[1-(cyclopropylmethyl)-5-ethanoyl-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridin-3-yl]amino]-~{N}-propan-2-yl-benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: crebbp bromodomain, transferase
• 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: 3
• 化学式量合計: 42319.44

構造登録者

Murray, J.M.,Boenig, G. (登録日: 2016-07-12, 公開日: 2016-11-02, 最終更新日: 2024-03-06)

主引用文献

Crawford, T.D.,Romero, F.A.,Lai, K.W.,Tsui, V.,Taylor, A.M.,de Leon Boenig, G.,Noland, C.L.,Murray, J.,Ly, J.,Choo, E.F.,Hunsaker, T.L.,Chan, E.W.,Merchant, M.,Kharbanda, S.,Gascoigne, K.E.,Kaufman, S.,Beresini, M.H.,Liao, J.,Liu, W.,Chen, K.X.,Chen, Z.,Conery, A.R.,Cote, A.,Jayaram, H.,Jiang, Y.,Kiefer, J.R.,Kleinheinz, T.,Li, Y.,Maher, J.,Pardo, E.,Poy, F.,Spillane, K.L.,Wang, F.,Wang, J.,Wei, X.,Xu, Z.,Xu, Z.,Yen, I.,Zawadzke, L.,Zhu, X.,Bellon, S.,Cummings, R.,Cochran, A.G.,Albrecht, B.K.,Magnuson, S.
Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.
J. Med. Chem., 59:10549-10563, 2016

PubMed Abstract: The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC = 0.02 μM, BRET IC = 0.41 μM, BRD4(1) IC = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.

PubMed: 27682507
DOI: 10.1021/acs.jmedchem.6b01022

実験手法

X-RAY DIFFRACTION (1.087 Å)