Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 40, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.127908
Keywords
Non-nucleoside DNA methyltransferase; inhibitors; DNMT1 inhibitors; DNMT3A inhibitors; Acute myeloid leukemia target
Categories
Funding
- National Science Foundation Grant [1808775]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1808775] Funding Source: National Science Foundation
Ask authors/readers for more resources
Screening of a small chemical library identified two structurally related DNMT3A inhibitors with low micromolar inhibition constants, suggesting an allosteric mechanism of action. These inhibitors could lead to the development of more selective drugs and show promising selectivity for DNMT3A.
Screening of a small chemical library (Medicines for Malaria Venture Pathogen Box) identified two structurally related pyrazolone (inhibitor 1) and pyridazine (inhibitor 2) DNMT3A inhibitors with low micromolar inhibition constants. The uncompetitive and mixed type inhibition patterns with DNA and AdoMet suggest these molecules act through an allosteric mechanism, and thus are unlikely to bind to the enzyme's active site. Unlike the clinically used mechanism based DNMT inhibitors such as decitabine or azacitidine that act via the enzyme active site, the inhibitors described here could lead to the development of more selective drugs. Both inhibitors show promising selectivity for DNMT3A in comparison to DNMT1 and bacterial DNA cytosine methyltransferases. With further study, this could form the basis of preferential targeting of de novo DNA methylation over maintenance DNA methylation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available