Abstract
Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current antiandrogen therapies induce resistant mutations at the hormone binding pocket (HBP) that convert the activity of these agents from antagonist to agonist. Thus, there is a high unmet medical need for the development of novel antiandrogens which circumvent mutation-based resistance. Herein, through the analysis of AR structures with ligands binding to the activation function-2 (AF2) site, we built a combined pharmacophore model. In silico screening and the subsequent biological evaluation lead to the discovery of the novel lead compound IMB-A6 that binds to the AF2 site, which inhibits the activity of either wild-type (WT) or resistance mutated ARs. Our work demonstrates structure-based drug design is an efficient strategy to discover new antiandrogens, and provides a new class of small molecular antiandrogens for the development of novel treatment agents against PCa.
Highlights
Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer death in men in the western countries (Torre et al, 2015)
We first generated a pharmacophore model based on the alignment of the Androgen receptor (AR) structures with the ligand binding to activation function-2 (AF2) site
Molecular docking, and subsequent bioassay, we identified IMB-A6 and its analogs as a new type of antiandrogen
Summary
Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer death in men in the western countries (Torre et al, 2015). As the disease evolves from androgen-sensitive cancer to castration-resistant prostate cancer (CRPC), the growth of cancer cells still rely on AR signaling axis (Jenster, 1999; Taplin, 2007). Current clinically used antiandrogens such as flutamide (FLU) (Goldspiel and Kohler, 1990), bicalutamide (BIC) (Blackledge et al, 1997), and recently approved enzalutamide (ENZ) (Semenas et al, 2013) mainly target the hormone binding pocket (HBP) of the AR LBD. These approved antiandrogens have greatly improved the survival and life
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