Aryl Hydantoin Heterocycle Compounds that Target the Androgen Receptor for Prostate Cancer Treatment

Prostate cancer is the most prevalent form of cancer among all men in the United States (US). It is also the second leading cause of cancer-related deaths in the US among men, largely due to the progressively treatment resistant nature of the disease. Treatment options for early stage prostate cancer include watchful waiting, radical prostatectomy, radiation therapy, and importantly androgen-deprivation therapy (ADT). Prostate cancer is dependent on androgen hormones, such as testosterone, for sustaining and promoting growth. Androgen hormones bind to the Androgen receptor (AR), causing AR localization to the nucleus where a complex is formed that regulates the transcription of critical genes. ADT is accomplished through administering an antagonist to the AR that blocks androgen ligands, or by castration (physical or chemical) to reduce the amount of testosterone. However, the disease frequently advances to castration resistant prostate cancer (CRPC), becoming resistant to these therapies by overexpressing AR. Additional anti-androgens have been developed, though these have had limited improvements in patient outcomes and are not effective against the refractory forms of prostate cancer. 

Recently, antiandrogenic diaryl thiohydantoin compounds have been shown to be more promising prostate cancer therapeutics. These compounds have shown success in clinical trials, though still with only mild improvement of patient outcomes. Therefore, more potent forms of these compounds are needed for improved therapies. Researchers at the National Cancer Institute (NCI) have developed aryl hydantoin derived heterocyclic compounds with improved efficacy as shown by in vitro and in vivo studies. These compounds include, most importantly, Androgen Receptor Inverse Agonists (ARIA), but also agonists and antagonists of the AR.   

NCI seeks research co-development partners and/or licensees to develop these compounds as therapeutics for prostate cancer. As these compounds consist of both AR agonists and antagonists, they may also be effective therapeutics for androgen dysfunctional disorders, such as androgen deficiency disorders or hyperandrogenism. 

Competitive Advantages:

• Increased potency compared with current prostate cancer therapeutic compounds
• Potency in disease models that are non-responsive to current prostate cancer therapeutics
• Potential to treat both early stage and advance stage prostate cancer
• Potential to treat a range of androgen receptor-positive solid tumors
• Other clinical trials with similar approaches provides promising human safety data

Commercial Applications:

• Therapeutic for 
  • Early and advanced stages of prostate cancer
  • Androgen receptor-positive breast cancer and other androgen receptor-positive solid tumors
  • Androgen deficiency disorders
  • Hyperandrogenism