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Invariably the tumor reappears and remains androgen driven despite castrate levels of circulating androgens. This occurs because the tumor adapts to make its own androgens and because of adaptive changes in the androgen receptor. These two mechanisms are targeted by abiraterone acetate (Zytiga®) and enzalutamide (Xtandi®), respectively. Each agent only prolongs survival by 3- 4 months and resistance to these agents occurs. Thus, better agents are sorely needed.
Recent work has identified nonsteroidal anti-inflammatory drugs (NSAIDs) as potent but non-specific inhibitors of AKR1C3, identifying existing drugs that could be redesigned as AKR1C3 inhibitors. To this end four different classes of SIMs have been developed as lead therapeutic agents:
Compounds in all four classes:
Compounds in Class 4 have the unexpected property of acting as AKR1C3 inhibitors and as androgen receptor antagonists making them bifunctional. Bifunctional agents have the potential to be superior to giving abiraterone and enzalutamide in combination.