title: A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer.
abstract: The LREX' prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor, glucocorticoid receptor (GR), which has similar DNA-binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand-binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX' cells, Py-Im polyamide interfered with both AR- and GR-driven gene expression, whereas enzalutamide interfered with only that of AR. Genomic analyses indicated immediate interference with the AR transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer.Cancer Res; 77(9); 2207-12. ©2017 AACR.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Kurmis
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Welch
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Nickols
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California. dervan@caltech.edu.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D009570:Nitriles; D009757:Nylons / Q000494:pharmacology*; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage; D011944:Receptors, Androgen / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D001549:Benzamides; D007093:Imidazoles; D009570:Nitriles; D009757:Nylons; D011758:Pyrroles; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D010669:Phenylthiohydantoin; C540278:enzalutamide