RT Journal Article SR Electronic T1 Small Molecule Targeting of PCNA Chromatin Association Inhibits Tumor Cell Growth JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.112.077735 DO 10.1124/mol.112.077735 A1 Zongqing Tan A1 Matthew Wortman A1 Kelsey L Dillehay A1 William L Seibel A1 Chris R Evelyn A1 Shanna J Smith A1 Linda H Malkas A1 Yi Zheng A1 Shan Lu A1 Zhongyun Dong YR 2012 UL http://molpharm.aspetjournals.org/content/early/2012/03/07/mol.112.077735.abstract AB Proliferating cell nuclear antigen (PCNA), a potential anti-cancer target, forms a homotrimer and is required for DNA replication and numerous other cellular processes. The purpose of this study was to identify novel small molecules that modulate PCNA activity to impact on tumor cell proliferation. An in silico screen of a compound library against a crystal structure of PCNA and a subsequent structural similarity search of the ZINC chemical database were carried out to derive relevant docking partners. Nine compounds, termed PCNA inhibitors (PCNA-Is), were selected for further characterization. PCNA-I1 selectively bound to PCNA trimers with a dissociation constant (Kd) of ~0.2-0.4 μM. PCNA-Is promoted the formation of sodium dodecyl sulfate (SDS)-refractory PCNA trimers. PCNA-I1 dose- and time-dependently reduced the chromatin associated PCNA in cells. Consistent with its effects on PCNA trimer stabilization, PCNA-I1 inhibited the growth of tumor cell of various tissue types with an IC50 of ~0.2 μM, whereas it affected the growth of non-transformed cells at significantly higher concentrations (IC50 ~1.6 μM). Moreover, uptake of BrdU was dose-dependently reduced in cells treated with PCNA-I1. Mechanistically the PCNA-Is mimicked the effect of PCNA knockdown by siRNA, inducing cancer cell arrest at both the S and G2/M phases. Thus, we have identified a class of compounds that can directly bind to PCNA, stabilize PCNA trimers, reduce PCNA association with chromatin, and inhibit tumor cell growth by inducing a cell cycle arrest. They are valuable tools in studying PCNA function and may be useful for future PCNA-targeted cancer therapy.