Work

Structural Investigations of Phthalazinone Derivatives as Allosteric Inhibitors of Human DNA Methyltransferase 3A

Year: 2024

Type: article

Abstract: The development of new therapeutics targeting enzymes involved in epigenetic pathways such as histone modification and DNA methylation has received a lot of attention, particularly for targeting diverse cancers. Unfortunately, irreversible nucleoside inhibitors (azacytidine and decitabine) have proven highly cytotoxic, and competitive inhibitors are also problematic. This work describes synthetic and structural investigations of a new class of allosteric DNA methyltransferase 3A (DNMT3A) inhibitors, leading to the identification of several critical pharmacophores in the lead structure. Specifically, we find that the tetrazole and phthalazinone moieties are indispensable for the inhibitory activity of DNMT3A and elucidate other modifiable regions in the lead compound.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.3c00528

Authors: Ivan Hernandez, Ethan Ward, Thomas R. R. Pettus, Norbert O. Reich

Institution: University of California, Santa Barbara

Language: English

Topic: Epigenetics and DNA Methylation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500