8P9I

Crystal structure of the first bromodomain of human BRD4 in complex with the dual BET/HDAC inhibitor NB462

PDB DOI: https://doi.org/10.2210/pdb8P9I/pdb

Classification: GENE REGULATION
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2023-06-06 Released: 2023-07-05
Deposition Author(s): Balourdas, D.I., Bauer, N., Knapp, S., Joerger, A.C., Structural Genomics Consortium (SGC)
Funding Organization(s): German Research Foundation (DFG)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.23 ?
R-Value Free: 0.193
R-Value Work: 0.167
R-Value Observed: 0.168

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization.

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.

(2024) ACS Chem Biol 19: 266-279

PubMed: 38291964 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acschembio.3c00427
Primary Citation of Related Structures:
8P9F, 8P9G, 8P9H, 8P9I, 8P9J, 8P9K, 8P9L

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 ₅₀ 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 HEXIM1 and proapoptotic p57 , both markers of BET inhibition. In addition, they have the potential to downregulate the oncogenic drivers of NUT midline carcinoma, as demonstrated for MYC and TP63 mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models.

Organizational Affiliation

Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.

Macromolecule Content

Total Structure Weight: 31.66 kDa
Atom Count: 2,529
Modelled Residue Count: 249
Deposited Residue Count: 254
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Bromodomain-containing protein 4	A, B	127	Homo sapiens	Mutation(s): 0 Gene Names: BRD4, HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens) Explore O60885 Go to UniProtKB: O60885
PHAROS: O60885 GTEx: ENSG00000141867
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O60885
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
X8T (Subject of Investigation/LOI) Query on X8T Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain I [auth B] MOL2 format, chain C [auth A] MOL2 format, chain I [auth B] mmCIF format, chain C [auth A] mmCIF format, chain I [auth B]	C [auth A], I [auth B]	~{N}-(2-aminophenyl)-4-(6-methyl-7-oxidanylidene-1~{H}-pyrrolo[2,3-c]pyridin-4-yl)benzamide C₂₁ H₁₈ N₄ O₂ JFWMIWHTKGVVSC-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain I [auth B] Interactions & Density Focus chain C [auth A] Focus chain I [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain J [auth B] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain P [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B]	D [auth A] E [auth A] F [auth A] G [auth A] H [auth A] D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], J [auth B], K [auth B], L [auth B], M [auth B], N [auth B], O [auth B], P [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B]