DNMT3A Small-Molecule Inhibitor Screen for Allosteric Inhibition of H3 Tail Binding Interactions

Project Description

DNA Methyltransferase 3A (DNMT3A) is an enzyme that establishes the methylation pattern essential for transcriptional regulation and cellular differentiation during embryonic development. However, DNMT3A can lead to various cancers, such as acute myeloid leukemia (AML), when not properly regulated by cellular binding partners. Current FDA approved drugs inhibit DNMT3A broadly and are highly toxic. Our project aims to discover new, specific, and non-toxic ways to control DNMT3A by targeting how it interacts with “histone code” post-translational markers. Using peptide synthesis tools at the BioPACIFIC MIP facilities, we will create fluorescein-labeled histone fragments to develop a fluorescence anisotropy-based assay to detect histone tail binding to DNMT3A. This assay will be used to screen a diverse chemical library to identify compounds that selectively block these interactions for novel drug development. Our synthesis and formulation efforts through BioPACIFIC can be applied to the greater BioPACIFIC community, enabling other research group to detect peptides/peptoids and assess their binding interactions with biological macromolecules.

Instruments