Professor, Medicinal Chemistry
The University of Kansas
Structure and Function of CYP17A1, a Critical Enzyme in Human Androgen Biosynthesis (2010-12)
Prostate cancer is the most common occurring cancer and the second-leading cause of cancer-related death for men in the United States. Progression is strongly linked to the presence of androgens. Traditional androgen deprivation therapy significantly decreases androgen production in prostate tissue, but fails to inhibit adrenal androgen synthesis, leaving a basal level of androgens in circulation. Cytochrome P450 17A1 (CYP17A1) is responsible for the conversion of pregnenolone to androgens in both tissues. Thus, inhibition of CYP17A1 provides a strategy for complete deprivation of androgens in the treatment of prostate cancer. Several CYP17A1 inhibitors are currently in trials, but there is currently no structural information about how these compounds bind CYP17A1. The lack of a CYP17A1 crystal structure prevents an understanding of how current inhibitors work and how they might be improved.
The objective of this proposal is to determine a structure of a CYP17A1/inhibitor complex to characterize how cytochrome P450 17A1 interacts with inhibitors currently in clinical trials and to provide a basis for improving these compounds. Understanding the interaction between CYP17A1 and its inhibitors would provide atomic level information about the binding interactions for inhibitors already in clinical trials. Furthermore, this information could be utilized in the design of improved CYP17A1 inhibitors. Our central hypothesis is that a crystal structure of CYP17A1 with inhibitor in the active site will reveal specific interactions that correspond to unique features of the enzyme. The specific aims are: 1) to engineer a soluble version of CYP17A1, 2) to optimize expression and purification strategies to generate mg quantities of pure, stable, functionally active, monodisperse CYP17A1 suitable for crystallization efforts, and 3) to grow diffraction-quality crystals of CYP17A1 with the inhibitor abiraterone or TOK-001 and determine the X-ray crystal structure. The expected outcome of the proposed study is the first crystal structure of the important steroid biosynthetic enzyme CYP17A1 in complex with clinically relevant inhibitors. This structure will enable a detailed understanding of inhibitor binding modes and provide a structure that can be utilized for the development of improved inhibitors.