5CPE

Crystal Structure of the first bromodomain of human BRD4 in complex with benzo[cd]indol-2(1H)-one ligand

Summary for 5CPE

• Entry DOI: 10.2210/pdb5cpe/pdb
• Related: 5C0I 5CP5 5CQT 5CRM 5CRZ 5CS8 5CTL
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, N-cycloheptyl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide, ... (4 entities in total)
• Functional Keywords: brd4, bromodomain, four alpha helices, transcription-transcr, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 17263.94

Authors

Zhang, Y.,Song, M.,Liu, Z.,Xue, X.,Xu, Y. (deposition date: 2015-07-21, release date: 2016-01-13, Last modification date: 2024-03-20)

Primary citation

Xue, X.,Zhang, Y.,Liu, Z.,Song, M.,Xing, Y.,Xiang, Q.,Wang, Z.,Tu, Z.,Zhou, Y.,Ding, K.,Xu, Y.
Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation
J.Med.Chem., 59:1565-1579, 2016

PubMed Abstract: The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

PubMed: 26731490
DOI: 10.1021/acs.jmedchem.5b01511

Experimental method

X-RAY DIFFRACTION (1.62 Å)