9IV5

BRD4 in complex with compound7

This is a non-PDB format compatible entry.

Summary for 9IV5

• Entry DOI: 10.2210/pdb9iv5/pdb
• Descriptor: Bromodomain-containing protein 4, 7-[2-fluoranyl-5-(oxetan-3-ylmethoxy)-3-(1,3,5-trimethylpyrazol-4-yl)phenyl]-1~{H}-imidazo[4,5-b]pyridine, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: primary reader for acetylated lysine residues, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15577.73

Authors

Du, Z.,Chen, X.,Cao, D.,Jiang, Z.,Xiong, B. (deposition date: 2024-07-23, release date: 2025-10-01)

Primary citation

Chen, X.,Kang, W.,Wu, T.,Cao, D.,Chen, Y.,Du, Z.,Yan, L.,Meng, F.,Wang, X.,You, Q.,Xiong, B.,Guo, X.,Jiang, Z.
Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy.
J.Med.Chem., 68:5719-5735, 2025

PubMed Abstract: Rational design of bromodomain (BD)-selective inhibitors could mitigate on-target toxicities associated with pan-BET inhibition but is challenging despite the availability of high-resolution structures. By simultaneously forming water bridges with BD1-specific residues in both the BC ring and the ZA channel, we identified a potent and orally bioavailable BET BD1-selective inhibitor , which exhibited a of 5.6 nM for BRD4 BD1 and a 214-fold selectivity for BRD4 BD1 over BD2. The cocrystal structure demonstrated a unique multi-water bridge mechanism involving BD1-specific residues K91- and D145-driven BD1 selectivity. extensively influenced the oncogene expression and metabolic pathway, including oxidative phosphorylation in MIA PaCa-2. , inhibited tumor growth and markedly augmented the therapeutic efficacy of the glycolysis inhibitor 2-DG. These findings illuminate that multi-water bridges enable design of BD1-selective inhibitors and a therapeutic strategy involving combined targeting of BD1-induced epigenetic reprogramming and glycolysis pathways for the management of pancreatic cancer.

PubMed: 40011026
DOI: 10.1021/acs.jmedchem.4c03069

Experimental method

X-RAY DIFFRACTION (1.59 Å)