DNMT-targeted library

ChemDiv’s library of small molecule compounds targeting DNA methyltransferases comprises 33,936 entries.

DNA methyltransferases (DNMTs) are essential enzymes that catalyze the addition of methyl groups to cytosine residues in DNA and serve as key epigenetic modifications known as DNA methylation. This process plays a critical role in various physiological functions, including gene expression regulation, embryonic development, X-chromosome inactivation, and the preservation of chromosome stability. By modulating the epigenetic landscape, DNMTs influence the accessibility of the DNA to the transcriptional machinery, thereby determining whether specific genes are turned on or off. The proper functioning of DNMTs is crucial for maintaining the delicate balance of gene expression patterns that support normal cell function and development.

Aberrations in DNMT activity can lead to dysregulated DNA methylation patterns, contributing to the development of diseases, particularly cancer. Overexpression or hyperactivity of DNMTs can result in the hypermethylation of CpG islands in the promoter regions of tumor suppressor genes, leading to their silencing and, consequently, uncontrolled cell growth and proliferation. This epigenetic alteration is a hallmark of various cancers, making DNMTs a focus of oncological research and drug development. Conversely, hypomethylation of DNA, often due to reduced DNMT activity, can lead to genomic instability and the activation of oncogenes, further contributing to tumorigenesis. Beyond cancer, aberrant DNMT activity has also been implicated in neurological disorders, autoimmune diseases, and developmental abnormalities, highlighting the broad impact of DNA methylation dysregulation on human health. Targeting DNMTs for therapeutic intervention offers a promising approach to correcting these aberrant methylation patterns and restoring normal gene function, underscoring the importance of understanding DNMT physiology and pathology.

Currently, DNMT has emerged as a pivotal target in drug discovery due to its central role in regulating DNA methylation patterns that affect gene expression, cell differentiation, and cell cycle progression. Targeting DNMTs offers a promising strategy for developing therapeutics, especially for cancers and other diseases where aberrant DNA methylation plays a critical role in disease progression. Inhibitors of DNMT can reverse abnormal gene silencing by reducing the hypermethylation of tumor suppressor gene promoters, thus restoring their expression and inhibiting tumor growth. This approach has been particularly beneficial in hematological malignancies and is being explored in solid tumors.

The benefits of targeting DNMT in drug discovery include the potential for reversing epigenetic modifications that contribute to the pathogenesis of various diseases, offering a mechanism to address the underlying causes directly rather than just treating symptoms. DNMT inhibitors, such as azacitidine and decitabine, have already been approved for the treatment of myelodysplastic syndromes and acute myeloid leukemia, demonstrating the clinical viability of this approach. Furthermore, targeting DNMTs opens up opportunities for combination therapies, where DNMT inhibitors are used alongside other anticancer agents to enhance therapeutic efficacy, overcome drug resistance, and achieve more durable responses. Beyond oncology, research into DNMT inhibitors for diseases characterized by epigenetic dysregulation, such as neurological disorders and autoimmune diseases, highlights the broad therapeutic potential of modulating DNA methylation. Thus, DNMTs represent a highly relevant target for drug discovery, offering pathways to novel treatments across a spectrum of diseases.

You can find examples of the DNMT-targeting scaffold in the slide deck above.