title: Novel small molecule guanidine Sigma1 inhibitors for advanced prostate cancer.
abstract: Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis of androgens. Recurrence is common and within 2-3years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies. In order to provide a more effective treatment, we are utilizing an approach that targets a key scaffolding protein, Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane protein that is critical in stabilizing the AR. Herein we report on a new series of Sigma1 compounds for lead optimization derived from a hybrid pharmacophore approach.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102-1101, USA. Electronic address: jsalvino@wistar.org.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Salvino
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102-1101, USA.
authors.forename: Yellamelli V V
authors.initials: YVV
authors.lastname: Srikanth
authors.affiliation: AstaTech, Inc., Keystone Business Park, 2525 Pearl Buck Road, Bristol, PA 19007, USA.
authors.forename: Rongliang
authors.initials: R
authors.lastname: Lou
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102-1101, USA.
authors.forename: Halley M
authors.initials: HM
authors.lastname: Oyer
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102-1101, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102-1101, USA.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000072237:ERG1 Potassium Channel / Q000737:chemistry / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D000072237:ERG1 Potassium Channel; D006146:Guanidines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: Guanidine; Prostate cancer; Sigma-1 chaperone; Sigma-1 receptor; Sigma1; Small molecule inhibitor