[HTML][HTML] Destroying the androgen receptor (AR)-potential strategy to treat advanced prostate cancer

R Narayanan, S Ponnusamy, DD Miller - Oncoscience, 2017 - ncbi.nlm.nih.gov
Oncoscience, 2017ncbi.nlm.nih.gov
Recently, a library of selective androgen receptor degraders (SARDs) that degrade the full
length and splice variant ARs (AR-SVs) through proteasome pathway was discovered and
characterized by our laboratory [1]. These molecules bind, antagonize, and degrade AR at
comparable sub-micromolar doses, making them potent small molecule degraders. The
SARDs represent a scaffold that might result in an AR conformation that promotes
degradation through ubiquitin proteasome pathway. Understanding that despite the typical …
Recently, a library of selective androgen receptor degraders (SARDs) that degrade the full length and splice variant ARs (AR-SVs) through proteasome pathway was discovered and characterized by our laboratory [1]. These molecules bind, antagonize, and degrade AR at comparable sub-micromolar doses, making them potent small molecule degraders. The SARDs represent a scaffold that might result in an AR conformation that promotes degradation through ubiquitin proteasome pathway. Understanding that despite the typical initial efficacy of androgen-deprivation therapy that the AR continues to play an important role in advance castration-resistant prostate cancer (CRPC) led to development of the nextgeneration AR competitive antagonist enzalutamide and the CYP17A1 inhibitor abiraterone [2]. This renewed interest in targeting the AR axis has significantly increased the efforts to discover AR antagonists. Men treated with enzalutamide and abiraterone yet are either non-responsive or develop resistance are heterogeneous in nature. Some of the observed phenotypes include a neuroendocrine type in which AR is not thought to be a driver, AR-SV-containing disease, a glucocorticoid receptor (GR)-positive subset, and others [3-4]. This heterogeneity of CRPC renders a challenge to design successful clinical trials and to develop next-generation AR-targeted drugs. Next-generation AR-targeting molecules that are in clinical development include ARN-509 (apalutamide)[5] and ODM-201 (darolutamide). These next-generation molecules are competitive AR antagonists with no additional mechanistic attributes that would otherwise distinguish them from enzalutamide, bicalutamide, and hydroxyflutamide. Therapeutic approaches with novel distinct mechanisms of action are required to treat the rapidly changing CRPC landscape and to slow the aggressively growing forms that significantly shorten overall survival. Molecules that are mechanistically distinct from competitive antagonists have the potential to have a significant therapeutic benefit. Although degraders to other nuclear receptors are available [6], AR degraders have been obscure and been difficult to discover and develop. Attempts to discover AR degraders have garnered interest in recent years for some of the potential mechanistic reasons depicted in Figure 1. The PROTAC technology (Arvinas) is a hybrid molecule, where a known ligand to a binding pocket is fused to an
E3 ligase-recruiting molecule. This chimera will bind to the ligand binding pocket of the target protein and will recruit E3 ligase to the protein ligand complex, resulting in protein degradation [7]. Degronomids (C4 therapeutics) and SNIPERS (Takeda) were designed utilizing a similar approach [8]. These chimeric molecules are potent with nanomolar to picomolar effective doses. An apparent disadvantage of these molecules is that their molecular weight is greater than 1000 Da, which according to Lipinski’s rule of five is an undesirable drug-like property for small molecules.
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