Target validation and structure-activity analysis of a series of novel PCNA inhibitors.
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.
Department of Internal Medicine, University of Cincinnati College of Medicine Cincinnati, OH, 45267.
Kelsey L
KL
Dillehay
Department of Pediatrics, Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, 46119.
William L
WL
Seibel
Department of Chemistry, University of Cincinnati College of Medicine Cincinnati, OH, 45219.
Daoli
D
Zhao
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine Cincinnati, OH, 45219.
Shan
S
Lu
Department of Internal Medicine, University of Cincinnati College of Medicine Cincinnati, OH, 45267.
Zhongyun
Z
Dong
Chromatin association; PCNA; inhibition of tumor cell growth; small molecule inhibitors; target validation