Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor–Chromatin Interactions

Abstract

Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists, such as enzalutamide, compete with androgens that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the development a series of small molecules that were rationally designed to selectively target the AR DNA binding domain (DBD) and, hence, to directly interfere with AR-DNA interactions. In the current work we have confirmed that the lead AR DBD inhibitor indeed directly interacts with the AR-DBD and tested that substance across multiple clinically relevant CRPC cell lines. We have also performed a series of experiments that revealed that genome-wide chromatin binding of AR was dramatically impacted by the lead compound (although with lesser effect on AR variants). Collectively, these observations confirm the novel mechanism of anti-androgen action of the developed AR-DBD inhibitors, establishing proof-of-principle for targeting DNA-binding domains of nuclear receptors in endocrine cancers.

Recent Advances in Prostate Cancer Treatment and Drug Discovery

“…In the vast majority of cases, the AR remains the main driver in CRPC and novel second-generation AR antagonists with improved efficacy to overcome resistance mechanisms and with reduced side-effects are in late-stage clinical testing [ 2 , 13 ]. Also, novel strategies to target different AR domains are being evaluated [ 50 , 51 , 52 ]. In addition, other pathways with an essential role in prostate cancer growth are being addressed.…”

“…The most advanced compound is ralaniten acetate (EPI-506) which was tested in clinical phase 1/2 for mCRPC [ 50 ]. Other approaches to block AR signaling deal with the binding function 3 located at the LBD surface and with a short region of the DBD for which small molecule inhibitors with in vitro or in vivo efficacy in several prostate cancer models have been identified [ 51 , 52 ].…”

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

“…Novel strategies that directly target the NR include blocking receptor interactions with specific coactivators (Azad et al 2015, Guy et al 2015, Foley & Mitsiades 2016, directly targeting NR binding to cognate DNA sequences or interfering with DBD dimerization (Dalal et al 2017), but also modulating ligand-independent functions (reviewed in Caboni & Lloyd 2013). Also along these lines, the AR-NTD has been explored as drug target for AR function control, in particular for management of its ligand-independent truncated variants (De Mol et al 2016, Imamura & Sadar 2016, Kumar et al 2016, Monaghan & McEwan 2016.…”

Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges

“…In recent years, development of novel drugs has been underway for efficient targeting of the above-described ligand-dependent and ligand-independent AR activation processes. These drugs include agents that antagonize the AR more strongly, degrade the AR, target the N-terminal and DNA-binding domain of the AR, or inhibit AR dimer formation [ 21 , 73 , 74 , 75 , 76 ] ( Table 1 ).…”