Pyrrole-imidazole (Py-Im) polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE)-targeted Py-Im polyamide significantly downregulates AR driven gene expression.
Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress.
PloS one. 2015 Nov 16*** epublish ***
Amanda E Hargrove, Thomas F Martinez, Alissa A Hare, Alexis A Kurmis, John W Phillips, Sudha Sud, Kenneth J Pienta, Peter B Dervan
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America. , Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America. , Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America. , Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America. , Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America. , Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America. , Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America. , Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.