DNA Methyltransferase (DNMT)
DNMT inhibitors' capacity to reverse epigenetic changes underlies their application in innovative leukemia therapies. Alfa Cytology provides development services for DNMT enzyme-targeting inhibitors. Our services focus on developing DNA demethylating agents that hinder DNMT enzyme activity in leukemia cells. Inhibiting DNMT enzymes is considered the optimal strategy for developing DNA demethylating agents for leukemia treatment.
Functional Roles of DNMT in Leukemia
Methylation of DNA is mediated by the DNMT protein family, which regulates de novo (DNMT3A and DNMT3B) and maintenance (DNMT1) methylation. Mutations in DNMT3A are observed in approximately 22% of acute myeloid leukemia (AML). DNA methyltransferase-1 is one of the members of DNA methyltransferases, in charge of maintaining established methylation.
Fig. 1. The function of DNA methyltransferase-1 in acute myeloid leukemia. (Li, M.; Zhang, D., 2022)
Discovery of DNMT Inhibitors for Leukemia
Based on the mechanism of action required for the development of DNMT inhibitors, we offer two types of inhibitor development: nucleoside inhibitors and non-nucleoside inhibitors.
- Nucleoside Inhibitors
Due to the modified pyrimidine ring in nucleoside analogs, which can be converted to nucleotides and incorporated into newly synthesized DNA or RNA, we provide development services for nucleoside analogs targeting DNMT enzymes to discover potential drug candidates for leukemia therapy. These nucleoside analogs include derivatives of cytidine and S-adenosyl-L-homocysteine (SAH). - Nonnucleoside Inhibitors
Non-nucleoside inhibitors directly interfere with the active site of DNMT, leading to inhibition of the enzyme's function. We offer assistance in the development of DNMT inhibitors targeting the catalytic pocket of DNMT. Our Natural Product Libraries and Small Molecule Library are specifically designed for screening non-nucleoside inhibitors, enabling us to perform candidate drug screening for our clients.
Development of DNMT Inhibitors for Leukemia
Discovery of DNMT1 Inhibitors
To identify potential DNMT1 inhibitors, we utilize a robust approach combining a high-throughput enzymatic activity assay and in silico screening. Our screening process explores a vast library of 1.8 million compounds, aiming to pinpoint those with the capability to effectively inhibit DNMT1 enzymatic activity.
Compound Binding and Inhibition of DNMT1
We synthesize candidate compounds through medicinal chemistry optimization to enhance potency, solubility, and lipophilicity. The selected compounds undergo biochemical and biophysical characterization using techniques such as radioactive SPA, photoaffinity labeling, and site-directed mutagenesis.
Leukemia Cell Growth
We evaluate candidate DNMT1 inhibitors on leukemia cell growth and viability using suitable cell lines. Our services include determining parameters such as gIC50, GDI, and generating dose-response curves, providing valuable insights into the impact of DNMT1 inhibitors on leukemia cells.
DNA Hypomethylation and Gene Activation
We analyze DNA methylation and gene expression changes in leukemia cells treated with DNMT1 inhibitors, providing clients with high-quality profiles and quantification of alterations. Valuable insights into epigenetic and transcriptional effects of DNMT1 inhibitors in leukemia cells are gained.
Advantages of Our Services
- We customize our services to meet your specific requirements and help you accomplish your research and development objectives.
- Our team of scientists comprises experts in the field of epigenetics and drug discovery.
- we work diligently to deliver results within agreed-upon timelines, ensuring that your project progresses smoothly.
- We have a wide range of leukemia cell lines and animal models to provide more options.
As a prominent provider in the field, Alfa Cytology specializes in offering services dedicated to the development of DNMT inhibitors tailored for leukemia therapy. Leveraging our profound knowledge in epigenetics and drug discovery, we provide extensive and integrated solutions to bolster your research and drug development initiatives focused on DNMT enzymes. Contact us to discuss your specific needs.
Reference
- Li, M.; Zhang, D. DNA methyltransferase-1 in acute myeloid leukaemia: beyond the maintenance of DNA methylation. Annals of Medicine. 2022, 54(1): 2011-2023.