Today, lysine demethylase enzymes (KDMs) are gaining increased attention as potential therapeutic targets. They are found to facilitate the removal of methyl marks from histone lysine residues, which regulates chromatin structure and gene expression. Accumulating evidence suggests that KDM4A is not only involved in maintaining body homeostasis, such as cell proliferation, migration, and tissue development, but it is also associated with several human diseases, especially cancers.
Our cheminformatics team has prepared a dedicated receptor-based Screening Library of over 2,000 potential lysine-specific demethylase 4A (KDM4A) inhibitors. The Library presented is a rich source of inhibitors for screening projects in KDM-related drug discovery.
The compound selection can be customized based on your requirements. Cherry-picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background information
Together with DNA methylation, histone modifications (including histone acetylation, methylation, phosphorylation, ubiquitination, etc.) represent the classical epigenetic mechanisms. Histones are targets of several posttranslational modifications (PTMs), such as methylation, acetylation, and phosphorylation, which can alter chromatin structure and accessibility, playing a critical role in epigenetic regulation and cell survival. Histone PTMs have been associated with various diseases, including cancer, metabolic syndromes, and neurological disorders.
Methylation plays a crucial role in several processes, such as cell differentiation and homeostasis, and, thus, it has a significant effect on the development and progression of various diseases. It primarily manifests itself on arginine and lysine residues and is mediated by multiple enzymes sharing common domains. Over 20 human histone N-methylated lysine residue demethylases (KDMs) have been identified, many of which exhibit altered expression patterns in cancer, neurological, and immunological diseases. As in the case of lysine methyltransferases, we can witness growing evidence suggesting that KDMs are involved in disease initiation and progression, which allows to categorize them as promising therapeutic targets [1]. The KDM4A isoform, in particular, makes a considerable contribution to epigenetic dysregulation in several cancers and is associated with disease aggressiveness and poor clinical outcomes.
Compound selection
This Screening Set was designed by applying computational chemistry and virtual screening techniques. A receptor-based virtual screening workflow based on known X-ray data for the complex with a pyrido[3,4-d]pyrimidin-4(3H)-one derivative was set up using the Schrödinger software. The bound ligand was extracted from the KDM4A crystal structure. Compounds from the Life Chemicals HTS Compound Collection were pre-filtered with in-house MedChem filters, including PAINS and toxicophore filters and the Rule of Five restrictions, and then docked in the active site (Fig. 1). The docking procedure implied constraining the two key features contributing to the ligand-binding - ligand-metal (Zn2+) coordination and the presence of a ligand’s hydrophobic moiety between side chains of Ty177 and Phe185 (Fig. 2). Initially, the screening procedure described above allowed to identify around 4,000 molecules, however, as a result of the subsequent manual evaluation of receptor-ligand complexes this number was narrowed down to 2,000 drug-like screening compounds.
Fig. 1. Docked compound F2949-0036 from the KDM4A Receptor Based Focused Library in the KDM4A active site. Intermolecular hydrogen bonds and Pi-Pi interactions are indicated.
Fig. 2. Metal coordination and hydrophobic positional constraints (2.8 Å radius) in the KDM4A active site
References:
1. Franci G, Sarno F, Nebbioso A, Altucci L. Identification and characterization of PKF118-310 as a KDM4A inhibitor. Epigenetics. 2017, 12(3):198-205