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Design and Optimization of Benzoic Acid Inhibitors Targeting the EBNA1 DNA-Binding Interface.

Garry R Smith¹, Mark E McDonnell¹, Yan Zhang¹

¹Fox Chase Therapeutics Discovery, Inc., 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.

ACS Medicinal Chemistry Letters

|July 14, 2026

Summary

Researchers developed a novel small molecule inhibitor targeting Epstein-Barr nuclear antigen 1 (EBNA1), a key protein in EBV-associated cancers. This inhibitor shows promise for treating viral malignancies and has advanced to clinical trials.

Keywords:

EBNA1 EBV Epstein−Barr virus SAR fragment-based design nasopharyngeal carcinoma

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Phthalic Acid Ester-Binding DNA Aptamer Selection, Characterization, and Application to an Electrochemical Aptasensor

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Published on: March 21, 2018

Area of Science:

Virology
Structural Biology
Medicinal Chemistry
Oncology

Background:

Epstein-Barr nuclear antigen 1 (EBNA1) is crucial for Epstein-Barr virus (EBV) episome maintenance.
EBNA1 is expressed in all EBV-associated malignancies, presenting a significant therapeutic target.
Targeting viral genome-maintenance proteins offers a novel strategy for antiviral and anticancer therapies.

Purpose of the Study:

To identify and optimize small molecule inhibitors of EBNA1 DNA binding.
To elucidate the structural basis for EBNA1 inhibition by small molecules.
To evaluate the therapeutic potential of EBNA1 inhibitors in preclinical models.

Main Methods:

Fragment-based screening and X-ray crystallography to identify initial binding scaffolds.
Structure-guided optimization through iterative medicinal chemistry.
In vitro assays to assess binding affinity and in vivo studies using EBV-positive xenograft models.

Main Results:

A 2,3-disubstituted benzoic acid scaffold was identified, binding to the EBNA1 DNA-binding interface.
Optimization led to compound 35 (VK-2019), a submicromolar inhibitor of EBNA1-DNA binding, featuring a 'lysine sandwich' interaction.
Compound 35 exhibited favorable drug-like properties and significant antitumor efficacy in preclinical models.

Conclusions:

The study defines key structural determinants for inhibiting EBNA1 DNA binding.
Compound 35 (VK-2019) represents a promising therapeutic candidate for EBV-associated malignancies.
A framework for targeting viral genome-maintenance proteins with small molecules has been established, advancing to clinical evaluation.