Prostate cancer is the leading cancer diagnosis in men, and the second-leading cause of male cancer-related death in America. Once this disease reaches its metastatic form, fatal progression is rapid and inevitable. These carcinomas require androgens for both growth and survival pathways. Targeting this, the androgen analog abiraterone acetate was approved in 2011 as a first-in-class treatment targeting the biosynthesis of androgen precursors via inhibition of the enzyme cytochrome P450 17A1 (CYP17), extending median survival time by ca. 5 months. Using abiraterone to stabilize CYP17, the Scott lab was able to solve a protein crystal structure of this complex. We set out to use this information to develop more effective and selective agents for this target.    Specifically, polar active site residues R239 and D298 lie within 5 � of the A and B rings of abiraterone's steroid backbone. Polar substitution revealed high-nanomolar inhibitory activity, but no improvement upon abiraterone. A ring-expansion strategy to better orient these substituents resulted in a crystal structure of improved resolution (2.25 �, from 2.7 � with abiraterone), revealing several key structural waters. Although the original hit lost activity, potency was increased through the addition of polar substituents able to make novel contacts with the protein backbone (confirmed with further crystallography), restoring abiraterone-like inhibitory activity.    Our process of structure-based ligand design, compound synthesis & profiling using inhibition assays, and protein crystallography are presented in an effort to identify novel binding interactions for CYP17-selective inhibitors.    An improvement we seek to make upon abiraterone-based CYP17 inhibition is to circumvent a virtually irreversible coordination with the active site metal, which is recognized as a common motif in nearly all cytochrome P450-targeted inhibitors. We are currently using the interactions identified through our inhibitor studies to design compounds that maintain activity despite the loss of this potent but nonselective Fe interaction.

Structure-based design of novel inhibitors of sex steroid biosynthesis targeting metastatic prostate cancer

246th National Meeting (2013)

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