Histone Methyltransferase EZH2 Targeted Library

Enhancer of zeste homolog 2 is a histidine-lysine N-methyltransferase. This enzyme plays an important role in histone methylation and transcriptional repression, and it can modulate downstream target gene expression through trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 interacts directly with other proteins to activate downstream genes in a manner that is independent of PRC2. Mutations or over-expression of EZH2 are associated with many forms of cancer, and EZH2 inhibitors are able to induce cell cycle arrest, apoptosis and cell differentiation in cells, as well as induction of genes involved in cell cycle regulation, apoptosis and neuronal-like differentiation. Thus, EZH2 enables to inhibit genes responsible for suppressing tumor development, and blocking its activity may slow down tumor growth. EZH2 is an attractive target for anticancer therapy.

In order to develop potent EZH2 inhibitors, BOC Sciences offers an enhancer of the EZH2 targeted library. It contains 979 compounds with predicted inhibitory activity against this enzyme.

Figure 1.A model depicting mechanism of overexpression of EZH2 in ovarian cancer and its role in regulating gene expression. (Jones, B.; et al. 2018)

Library Design

Design Process

BOC Sciences has combined various ligand-based virtual screening approaches to design the EZH2 target library.

1. Firstly, we divide the known EZH2 inhibitors into two clusters, and then randomly divided the compounds of each cluster into a training set and a test set
2. The training set is used to develop Bayesian and artificial neural network models, and the training set is also applied as a template for compounds selection with k-NN based on different fingerprints. The test set is used to validate the Bayesian models and neural networks
3. Then, nine training sets are created from active EZH2 inhibitors for pharmacophore modeling, and the models are optimized and validated using both active and inactive EZH2 inhibitors
4. Our scientists perform a pharmacophore screening against the optimized model
5. The highest scored compounds from the pharmacophore screening are crossed with the highest scored compounds obtained by applying machine learning methods, and visual analysis

Design Strategy

1. Machine Learning
• Bayesian models and artificial neural networks based on different molecular descriptors: Fingerprints, number of rings, number of hydrogen donors and acceptors, molecular weight, number of rotatable bonds, LogP, PSA, topological descriptors, etc
• K-nearest neighbor algorithm
2. Pharmacophore modeling

The combination of artificial neural networks, Bayesian statistics, k-NN and pharmacophore modeling allows increasing the number of active compounds identified during the screening process

Histone Methyltransferase EZH2 Targeted Library Characteristics

• No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
• Unique small molecule regulators with biological activity for epigenetic studies and related assays
• The library contains epigenetics-related compounds targeting HDAC, histone demethylases, histone acetyltransferases (HAT), DNA methyltransferases (DNMT), epigenetic reader domains, microRNAs, etc
• Valuable tool for epigenetic target identification in chemogenomics, pharmacogenomics and other biological applications
• Bioactivity and safety confirmed by preclinical studies and clinical trials
• Structural diversity, medicinal activity, and cellular penetration
• Structural document, IC₅₀, and other chemical and biological data are provided
• All compounds are continually updated
• All of these compounds with Tanimoto index ≥ 0.85
• Compound cherry-picking service is provided

What We Deliver

• Delivered within 2 weeks in any customer-preferred format
• Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
• All compounds have a minimum purity of 90% assessed by ¹H NMR and HPLC
• Analytical data is provided

BOC Sciences provides professional, rapid and high-quality services of Histone Methyltransferase EZH2 Targeted Library design at competitive prices for global customers. Personalized and customized services of Histone Methyltransferase EZH2 Targeted Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!