title: Small-molecule targeting of proliferating cell nuclear antigen chromatin association inhibits tumor cell growth.
abstract: 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 (K(d)) 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 IC(50) of ~0.2 μM, whereas it affected the growth of nontransformed cells at significantly higher concentrations (IC(50), ~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 G(2)/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.
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Zongqing
authors.initials: Z
authors.lastname: Tan
authors.forename: Matthew
authors.initials: M
authors.lastname: Wortman
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Dillehay
authors.forename: William L
authors.initials: WL
authors.lastname: Seibel
authors.forename: Chris R
authors.initials: CR
authors.lastname: Evelyn
authors.forename: Shanna J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Linda H
authors.initials: LH
authors.lastname: Malkas
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002843:Chromatin; D018809:Proliferating Cell Nuclear Antigen