5KU3

BRD4 bromodomain in complex with Cpd59 ((S)-1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone)

Summary for 5KU3

• Entry DOI: 10.2210/pdb5ku3/pdb
• Related: 5KTW 5KTX
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, DIMETHYL SULFOXIDE, ... (7 entities in total)
• Functional Keywords: brd4 bromodomain, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 16091.53

Authors

Murray, J.M.,Huang, W. (deposition date: 2016-07-12, release date: 2016-11-02, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.14 Å)