981 TARGETING ANDROGEN RECEPTOR-DEPENDENT PROSTATE CANCER WITH MULTIVALENT ETHISTERONE CONJUGATES

Abstract

INTRODUCTION AND OBJECTIVES: Prostate cells are dependent on androgens for growth and survival and thus the androgen receptor (AR) is the major therapeutic target in prostate cancer. While prostate cancers are treated with agents that inhibit androgen synthesis and modulate AR activity, the aggressive disease state called castration resistant prostate cancer (CRPC) is resistant to treatment. Studies indicate that AR itself promotes treatment resistance. Men with CRPC have a poor prognosis, suggesting that the AR directs alternate programs of gene transcription. To circumvent drug resistance, new therapeutic agents for prostate cancer should possess mechanisms of action that are distinct from those of current approaches. Our objective is to test whether multiple ethisterone ligands conjugated to peptoid oligomers will inhibit AR activity and repress prostate cancer growth. METHODS: Using an N-substituted glycine oligomer scaffold, termed a “peptoid,” we conjugated ethisterone, a 17 -ethynyl homologue of DHT, to peptoid side chains, and generated a set of multivalent conjugates that differed in valency, spacing and conformational ordering. Multivalent pharmacological strategies are advantageous because they enhance binding to target receptors through avidity effects. We tested these compounds for effects on AR transcriptional activity and cellular proliferation using LNCaP-abl cells, a model for CRPC. RESULTS: We identified a linear and a cyclic peptoid divalent conjugate (Fig 1) that exhibit potent and distinct anti-proliferative effects in LNCaP-abl cells. The linear compound blocks AR action by competing for androgen binding, deterring AR translocation into the nucleus, and preventing AR?s ability to activate a pro-cancer gene signature. In contrast, the cyclic conjugate, despite its inability to compete for androgen binding to AR, promotes AR nuclear localization but alters the cell cycle, causing cancer cell death. CONCLUSIONS: Our studies show that the multivalent conjugates exhibit promise as potential therapeutic agents for treatmentresistant prostate cancer.