Prostate cancer is a leading cause of cancer mortality in U.S. men.  Cytochrome P450 17A1 (CYP17A1) is a key multifunctional enzyme in the synthesis of steroid androgens responsible for prostate cancer proliferation.  Specifically, CYP17A1 first accomplishes a 17a-hydroxylation essential for androgen and glucocorticoid production.  Subsequently the enzyme also performs a second, mechanistically-distinct lyase reaction cleaving the 17-acyl group from 17a-hydroxypregnenolone that is required only to generate androgens.  The first FDA-approved CYP17A1 inhibitor inhibits both reactions, thus obliterating androgen production, but also disrupting glucocorticoid and mineralocorticoid levels.  However distinct mechanisms for CYP17A1 hydroxylation and lyase reactions raise the potential to inhibit just the latter androgen-producing capability.  Recent structures of CYP17A1 provided the opportunity to examine ligand interactions with the enzyme, suggesting key structural and chemical features of the protein, substrates, and inhibitors.  Structures with steroidal CYP17A1 inhibitors currently in use and in development suggest the structural basis of potentially problematic promiscuous inhibitor binding to the androgen receptor.  Comparison of CYP17A1 complexes with inhibitors that alter both enzymatic reactions versus CYP17A1 complexes with inhibitors that decimate only the lyase reaction suggest critical residues in a hydrogen bonding network likely to control enzyme reactivities.  Site-directed mutagenesis of active site residues and those in the putative cytochrome b5 binding site, and analysis of naturally-occurring mutations from patients with steroidogenic disease have provided orthogonal routes to dissect the structural and functional interactions that control the two disparate reactions within the single CYP17A1 active site.  This information is expected to inform the design of inhibitors that are not only selective for CYP17A1 over other enzymes in the steroidogenic pathway, but are also selective inhibitors of the enzyme's lyase reaction.  Such enzyme-selective and reaction-selective inhibitors would be optimal for the treatment of metastatic prostate cancer with reduced off-target and off-pathway side effects.

Structures and function of cytochrome P450 17A1:  Drug target for metastatic prostate cancer

245th National Meeting (2013)

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