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Updated: Apr 16, 2026
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Target validation and structure-activity analysis of a series of novel PCNA inhibitors
Kelsey L Dillehay1, William L Seibel2, Daoli Zhao3
1Department of Internal Medicine, University of Cincinnati College of Medicine Cincinnati, OH, 45267.
Abstract:
Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 was most potent. The purpose of this study is to further establish targeting of PCNA by PCNA-I1 and to identify PCNA-I1 analogs with superior potencies. We found that PCNA-I1 does not affect the level of chromatin-associated PCNA harboring point mutations at the predicted binding site of PCNA-I1. Forty-six PCNA-I1 analogs with structures of 1-hydrazonomethyl-2-hydroxy (scaffold A), 2-hydrazonomethyl-1-hydroxy (scaffold B), 2-hydrazonomethyl-3-hydroxy (scaffold C), and 4-pyridyl hydrazine (scaffold D) were analyzed for their effects on cell growth in four tumor cell lines and PCNA trimer stabilization. Compounds in scaffold group A and group B showed the highest trimer stabilization and the most potent cell growth inhibitory activities with a significant potency advantage observed in the Z isomers of scaffold A. The absence of trimer stabilization and growth inhibitory effects in compounds of scaffold group D confirms the essentiality of the hydroxynaphthyl substructure. Compounds structure-activity relationship (SAR)-6 and SAR-24 were analyzed for their effects on and found to reduce chromatin-associated PCNA in tumor cells. This study led to the identification of SAR-24, a compound with superior potencies and potentially improved solubility, which will be used for future development of PCNA-targeting cancer therapies.
Insights
Proliferating cell nuclear antigen inhibitors (PCNA-Is) target tumor cells by stabilizing PCNA trimers and inhibiting growth. New analogs, particularly scaffold A Z-isomers like SAR-24, show enhanced potency for cancer therapy development.
Area of Science:
- Molecular Biology
- Cancer Therapeutics
- Drug Discovery
Background:
- Proliferating cell nuclear antigen (PCNA) is crucial for DNA replication and repair, with elevated levels in tumor cells making it a promising cancer therapy target.
- Previous research identified nine PCNA inhibitors (PCNA-Is) that bind PCNA, stabilize its trimer structure, reduce chromatin-associated PCNA, and inhibit tumor cell growth, with PCNA-I1 being the most potent.
Purpose of the Study:
- To further validate PCNA as a therapeutic target using PCNA-I1.
- To identify novel PCNA-I1 analogs with enhanced potency for cancer treatment.
Main Methods:
- PCNA-I1's effect on chromatin-associated PCNA was assessed in cells with mutated PCNA binding sites.
- Forty-six PCNA-I1 analogs across four scaffolds (A, B, C, D) were synthesized and analyzed for tumor cell growth inhibition and PCNA trimer stabilization.
- Structure-activity relationships (SAR) were investigated, focusing on specific analogs like SAR-6 and SAR-24 for their impact on chromatin-associated PCNA.
Main Results:
- PCNA-I1 did not affect chromatin-associated PCNA in cells with mutations at the predicted binding site.
- Scaffolds A and B compounds demonstrated the highest PCNA trimer stabilization and potent tumor cell growth inhibition, with Z-isomers of scaffold A showing a significant advantage.
- Scaffold D compounds lacked trimer stabilization and growth inhibition, highlighting the importance of the hydroxynaphthyl substructure; SAR-24 emerged as a potent analog with potential for improved solubility.
Conclusions:
- The study confirms PCNA as a viable target and identifies specific structural features crucial for PCNA inhibitor activity.
- Novel PCNA-I1 analogs, particularly SAR-24, exhibit superior potency and are promising candidates for developing new PCNA-targeting cancer therapies.
