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Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
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Enzyme Inhibition

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Related Experiment Video

Updated: Jun 11, 2025

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells.

Mélanie Uguen, Devan J Shell, Madhushika Silva

Biorxiv : the Preprint Server for Biology

|October 10, 2024

Summary

Researchers developed UNC10013, a potent covalent ligand targeting the SETDB1 triple Tudor domain (3TD). This selective molecule modulates SETDB1 activity in cells, offering a new tool for studying cancer and neurodegenerative diseases.

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Last Updated: Jun 11, 2025

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

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Published on: August 5, 2022

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A High-Throughput Enzyme-Coupled Activity Assay to Probe Small Molecule Interaction with the dNTPase SAMHD1

A High-Throughput Enzyme-Coupled Activity Assay to Probe Small Molecule Interaction with the dNTPase SAMHD1

Published on: April 16, 2021

Area of Science:

Biochemistry
Chemical Biology
Epigenetics

Background:

SETDB1 (SET Domain Bifurcated 1) is a key epigenetic regulator implicated in cancer and neurodegenerative diseases.
The triple Tudor domain (3TD) of SETDB1 functions as a reader of lysine methylation marks, crucial for its biological functions.

Purpose of the Study:

To identify and characterize small molecule ligands targeting the SETDB1 3TD.
To develop a potent and selective covalent inhibitor for studying SETDB1's role in disease.

Main Methods:

High-throughput screening to identify initial ligands.
Structure-based drug design and chemical optimization.
Biochemical assays to determine ligand potency and selectivity.
Cell-based assays to assess target engagement and functional effects.

Main Results:

Discovery of UNC6535, a dual TD2/TD3 binder.
Development of UNC10013, the first covalent 3TD ligand targeting Cys385.
UNC10013 exhibits high potency (k _inact /K _I = 1.0 x 10 ⁶ M ^-1 s ^-1) and proteome-wide selectivity.
UNC10013 acts as a negative allosteric modulator of SETDB1-mediated Akt methylation in cells.

Conclusions:

UNC10013 is a potent, selective, and cell-active covalent ligand for the SETDB1 3TD.
This compound demonstrates negative allosteric modulator properties.
UNC10013 serves as a valuable chemical probe for investigating SETDB1's biological roles in disease progression.