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Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer
Sandra C Ordonez-Rubiano1, Chad A Maschinot1, Sijie Wang1
1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University. Robert Heine Pharmacy Building 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
Abstract:
Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromodomain-containing protein 7 (BRD7) is implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two inhibitors with increased selectivity toward BRD7, 1-78 and 2-77, which bind with submicromolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands occupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.
Insights
Researchers developed selective chemical probes for Bromodomain-containing protein 7 (BRD7), a protein implicated in cancer. These novel inhibitors target a unique binding pocket, offering new tools to study BRD7
Area of Science:
- Biochemistry
- Molecular Biology
- Chemical Biology
Background:
- Bromodomain-containing proteins are epigenetic readers of acetylated lysine.
- Bromodomain-containing protein 7 (BRD7) is involved in various cancers.
- Selective chemical probes for BRD7 are currently lacking.
Purpose of the Study:
- To identify and develop selective chemical probes for Bromodomain-containing protein 7 (BRD7).
- To investigate the function of BRD7 in cancer through chemical biology approaches.
Main Methods:
- Utilized crystal structures of BRD7 and BRD9 bromodomains (BDs).
- Designed and synthesized ligands targeting a BRD7-exclusive binding pocket.
- Performed binding affinity assays and binding mode analyses.
- Validated compound selectivity and utility in cell-based prostate cancer models.
Main Results:
- Identified a unique binding pocket exclusive to BRD7.
- Developed two selective BRD7 inhibitors, 1-78 and 2-77, with submicromolar affinity.
- Demonstrated that inhibitors occupy a unique cleft and maintain key interactions.
- Validated compound selectivity and efficacy in prostate cancer cell models.
Conclusions:
- Developed the first selective chemical probes for BRD7.
- These probes provide valuable tools for studying BRD7's role in cancer.
- The findings pave the way for further investigation into BRD7-targeted therapies.
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