8P9J

Crystal structure of the first bromodomain of human BRD4 in complex with the dual BET/HDAC inhibitor NB500

Summary for 8P9J

• Entry DOI: 10.2210/pdb8p9j/pdb
• Descriptor: Bromodomain-containing protein 4, ~{N}-(2-aminophenyl)-5-(6-methyl-7-oxidanylidene-1~{H}-pyrrolo[2,3-c]pyridin-4-yl)pyridine-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain, epigenetic drugs, inhibitor, cancer therapy, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15893.24

Authors

Balourdas, D.I.,Bauer, N.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2023-06-06, release date: 2023-07-05, Last modification date: 2024-06-26)

Primary citation

Bauer, N.,Balourdas, D.I.,Schneider, J.R.,Zhang, X.,Berger, L.M.,Berger, B.T.,Schwalm, M.P.,Klopp, N.A.,Siveke, J.T.,Knapp, S.,Joerger, A.C.
Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization.
Acs Chem.Biol., 19:266-279, 2024

PubMed Abstract: Bromodomain and extra-terminal domain (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors, such as pancreatic cancer. Here, we developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC values in the 100 nM range in cellular NanoBRET target engagement assays. For one of our lead molecules, we could also show the selective inhibition of HDAC1/2 over all other zinc-dependent HDACs. Importantly, this on-target activity translated into promising efficacy in pancreatic cancer and NUT midline carcinoma cells. Our lead molecules effectively blocked histone H3 deacetylation in pancreatic cancer cells and upregulated the tumor suppressor and proapoptotic , both markers of BET inhibition. In addition, they have the potential to downregulate the oncogenic drivers of NUT midline carcinoma, as demonstrated for and mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models.

PubMed: 38291964
DOI: 10.1021/acschembio.3c00427

Experimental method

X-RAY DIFFRACTION (1.42 Å)