PT  - JOURNAL ARTICLE
AU  - Zongqing Tan
AU  - Matthew Wortman
AU  - Kelsey L. Dillehay
AU  - William L. Seibel
AU  - Chris R. Evelyn
AU  - Shanna J. Smith
AU  - Linda H. Malkas
AU  - Yi Zheng
AU  - Shan Lu
AU  - Zhongyun Dong
TI  - Small-Molecule Targeting of Proliferating Cell Nuclear Antigen Chromatin Association Inhibits Tumor Cell Growth
AID  - 10.1124/mol.112.077735
DP  - 2012 Jun 01
TA  - Molecular Pharmacology
PG  - 811--819
VI  - 81
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/81/6/811.short
4100  - http://molpharm.aspetjournals.org/content/81/6/811.full
SO  - Mol Pharmacol2012 Jun 01; 81
AB  - Proliferating cell nuclear antigen (PCNA), a potential anticancer 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 affect 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 to 0.4 μM. PCNA-Is promoted the formation of 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 cells of various tissue types with an IC50 of ∼0.2 μM, whereas it affected the growth of nontransformed 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.