Epigenetic regulation is fundamental in controlling gene expression without altering the DNA sequence. It involves chemical modifications to DNA and histone proteins, which influence various biological processes and are implicated in numerous diseases such as cancer, neurological disorders, and autoimmune conditions. DNA-encoded libraries (DELs) have emerged as a powerful tool in this domain, offering a high-throughput and efficient approach to discovering novel compounds that can modulate epigenetic targets.
Screening Strategies for Epigenetic Targets Using DELs
The screening strategies for nuclear receptors using DELs encompass a comprehensive approach, including:
High-Throughput Screening
DELs technology enables the screening of billions of compounds simultaneously, a crucial advantage for identifying modulators of epigenetic targets like histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and bromodomain-containing proteins (BETs). The DNA encoding serves as a unique identifier for each compound, allowing for the rapid and efficient identification of active compounds.
Iterative Enrichment
The iterative nature of DELs screening allows for multiple rounds of selection and enrichment. This process enhances the binding affinity and specificity of compounds towards the target epigenetic proteins. Initial hits are refined through successive rounds, leading to the optimization of lead compounds with improved potency and selectivity.
Targeting Protein-Protein Interactions
Epigenetic regulation frequently involves protein-protein interactions (PPIs). DELs are particularly effective in identifying small molecules that disrupt these interactions. For example, inhibitors of BET bromodomains prevent BET proteins from binding to acetylated histones, thus modulating gene expression.
Examples of DELs Screen for Epigenetic Targets
HDAC Inhibitors
Histone deacetylases (HDACs) play a pivotal role in regulating gene expression by removing acetyl groups from histone proteins. In one study [1], DELs screening had led to the discovery of novel HDAC inhibitors, which had shown efficacy in cancer treatment. Compounds identified through DELs have demonstrated potent activity against various cancer cell lines, highlighting their therapeutic potential.
BET Bromodomain Inhibitors
Bromodomain and extra-terminal (BET) proteins recognize acetylated lysines on histones, facilitating the recruitment of transcriptional machinery to chromatin. One case study [1] highlighted the discovery of the BET inhibitor JQ1 with DELs screening. BET inhibitors have shown promise in treating cancers and inflammatory diseases, underscoring the utility of DELs in epigenetic drug discovery.
Advantages of DELs in Epigenetic Targets
- Expansive Chemical Space: DELs offer access to a vast chemical space, increasing the likelihood of identifying unique and potent modulators for epigenetic targets.
- Efficiency and Speed: The high-throughput nature of DELs screening accelerates the drug discovery process. Researchers can rapidly identify and optimize lead compounds, significantly reducing the time required to develop new therapeutics.
- Cost-Effectiveness: The use of DNA encoding allows for the simultaneous screening of vast libraries, reducing the need for extensive reagent and resource consumption.
- Mechanistic Insights: DELs screening provides valuable mechanistic insights into the interactions between small molecules and epigenetic targets. By analyzing the binding interactions, researchers can gain a deeper understanding of how these compounds modulate epigenetic regulation.
The ability of DNA-encoded libraries (DELs) to screen extensive libraries rapidly and iteratively optimize hits makes them particularly well-suited for the complex field of epigenetics. Contact us today to learn more about our services and discover how we can empower your journey towards innovation and success.
Reference
- Jeong S, Kim HR, Shin JH, et al. Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins. Mol Ther Nucleic Acids. 2023 Apr 24;32:637-649.