Related Experiment Video
Updated: Mar 19, 2026
07:26
Site Specific Lysine Acetylation of Histones for Nucleosome Reconstitution using Genetic Code Expansion in Escherichia coli
Published on: December 26, 2020
4.5K
A bivalent lysine-acetylated small-molecule binding site in MYC.
Biorxiv : the Preprint Server for Biology
|March 18, 2026
Summary
Researchers identified a new binding site on the MYC protein, crucial for developing small-molecule inhibitors (MYCi) targeting cancer. This discovery offers a promising strategy for MYC-targeted cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The MYC oncoprotein is a critical cancer driver but lacks druggable pockets, hindering therapeutic development.
- Understanding MYC's structure and interactions is key to designing effective cancer treatments.
Purpose of the Study:
- To identify and characterize a novel binding site on the MYC protein for small-molecule inhibitors.
- To investigate the role of MYC acetylation in inhibitor binding and efficacy.
Main Methods:
- CRISPR-tiling mutagenesis was employed to identify resistance mutations.
- Biophysical methods were used to assess inhibitor binding affinity.
- Gene expression analysis was performed to evaluate the effects of the inhibitor.
Main Results:
- A bivalent binding site formed by the bHLH domain and eMBII region of MYC was identified.
- Mutations conferring resistance were mapped to the bHLH and eMBII regions.
- Acetylation of lysine K148 enhanced inhibitor binding and modulated MYC's oncogenic activity.
- The small-molecule inhibitor (MYCi) selectively targeted genes regulated by acetylated MYC.
Conclusions:
- A high-affinity small-molecule MYC inhibitor (MYCi) binding site has been characterized.
- MYCi selectively targets acetylated, oncogenic MYC, providing a rationale for novel cancer therapies.
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