Histone Deacetylases (HDAC) Targeted Library

Description

ChemDiv’s histone deacetylase (HDAC) targeted library contains 9,500 compounds.

Regulation of gene expression is a complex process governed by multiple mechanisms, including DNA methylation, ATP-dependent chromatin remodeling, and various post-translational modifications (PTMs) of histones. Among these, the dynamic acetylation and deacetylation of ε-amino groups of lysine residues within the tail regions of core histones stand out as a key regulatory mechanism. Histones, which are the primary protein constituents of chromatin, play a fundamental role in stabilizing the nucleosome core and are subject to a wide array of specific PTMs.

The reversible acetylation and deacetylation of nucleosomal histones are particularly crucial for the modulation of chromatin structure and function, ultimately impacting the regulation of gene expression. These modifications affect the interaction between histones and DNA, making chromatin more or less accessible to transcription factors and other regulatory proteins, thereby influencing gene activity. The enzymes responsible for adding acetyl groups to histones are known as histone acetyltransferases (HATs), while histone deacetylases (HDACs) remove these acetyl groups. This reversible process not only plays a pivotal role in controlling gene expression but also in various cellular processes, including DNA repair, replication, and cell cycle progression. Given its importance, the regulation of histone acetylation and deacetylation has become a significant focus of research, particularly in the context of understanding and treating human diseases where these processes are dysregulated, such as cancer, neurological disorders, and inflammatory conditions.

HDACs play a central role in drug discovery due to their critical function in regulating gene expression through the removal of acetyl groups from histone proteins, influencing chromatin structure and accessibility. Dysregulation of HDAC activity is implicated in a variety of diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, making them attractive targets for therapeutic intervention. Inhibitors of HDACs have shown promise in modulating aberrant gene expression patterns associated with these diseases, leading to the development and approval of several HDAC inhibitors as cancer therapeutics. The exploration of HDACs in drug discovery extends beyond oncology, with ongoing research investigating their potential in treating neurological disorders, such as Huntington's and Alzheimer's diseases, as well as inflammatory disorders, by restoring normal acetylation patterns, thus correcting misregulated gene expression and cellular dysfunction. HDACs' pivotal role in epigenetic regulation positions them as key targets for developing novel therapeutics aimed at modulating gene expression to treat a broad spectrum of diseases.

Our highly curated library of small molecule compounds specifically targeted at HDACs offers a powerful tool for drug discovery, providing a focused approach to exploring the therapeutic potential of modulating epigenetic mechanisms. By selectively inhibiting HDACs, these compounds can correct aberrant gene expression patterns associated with a range of diseases, including various cancers, neurodegenerative disorders, and inflammatory conditions. Such a library facilitates the rapid screening and identification of HDAC inhibitors with optimized efficacy and specificity, accelerating the development of novel therapeutics. It enables researchers to dissect the complex roles of different HDAC isoforms in disease pathology, aiding in the design of isoform-specific inhibitors that minimize off-target effects and improve therapeutic outcomes. This targeted library not only enhances the efficiency of drug discovery processes but also opens new avenues for personalized medicine by providing compounds that can be tailored to the epigenetic landscape of individual patients' conditions.

Publications

1. Luckhurst C.A., et al. Potent, Selective, and CNS Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors. ACS Med Chem Lett. 2015;7(1):34 39.

2. Luckhurst CA, et al. Development and characterization of a CNS penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor. Bioorg Med Chem Lett. 2019;29(1):83 88.

3. Blum C.A., Jarpe M.B. Isoform Selective Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancer. Chapter 13, Medicinal Chemistry Reviews 2018; 53:245 264.

4. Wagner F.F., et al. Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors. Bioorg . Med. Chem. 2016;24(18):4008 4015.

5. Ferreira de Freitas R., et al. Identification and Structure Activity Relationship of HDAC6 Zinc Finger Ubiquitin Binding Domain Inhibitors. J. Med. Chem. 2018;61(10):4517 4527.