Thinking outside the NR box : advancing novel non ligand binding pocket antagonists for the human androgen receptor

Abstract

Current treatment of prostate cancer (PCa) typically involves administration of 'classical' antiandrogens, competitive inhibitors of natural androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand binding pocket (LBP) in the C-terminal ligand binding domain (LBD) of the AR. However, prolonged LBP-targeting can often lead to androgen resistance and alternative therapies and therapeutic strategies are urgently required. We advance evidence that alternative non LBP-mediated modulation of the AR with selective small molecule scaffolds can directly disrupt the AR coactivator interaction, affording the possibility to overcome the problem of androgen resistance. Here, we report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of the AR interaction with coactivators through application of structure and ligand-based virtual screening. Lead optimization and SAR studies for this novel class of compounds are reported by the application of an in silica protocol combining induced fit docking and MM-GB(PBSA) methods, and by biological validation with time-resolved fluorescence resonance energy transfer (TR-FRET) techniques as a primary screen. The novel diarylhydrazides reported demonstrate full ('true') antagonism in AR with low micromolar potency, high selectivity over both the Estrogen Receptors alpha and beta (ERα and ERβ) and the Glucocorticoid Receptor (GR) and only micromolar partial antagonism in the Progesterone Receptor (PR). The lead compound, MDG506 demonstrates efficacy with low determined toxicity in different PCa cellular models and reduces DHT induced or 'classical' antiandrogen induced prostate specific antigen (PSA) expression in a dose responsive fashion. These data provide compelling evidence for such non-LBP intervention as an alternative approach to classical PCa therapy.