Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001

Abstract

The structures of CYP17A1 with steroid inhibitors abiraterone or TOK-001 provide a better understanding of the enzyme’s catalytic capabilities and inhibition, and hence assist in understanding steroidogenic diseases and designing drugs to improve the treatment of prostate and other steroid-responsive cancers. The membrane-bound enzyme cytochrome P450 17A1 (CYP17A1) catalyses the biosynthesis of androgens in humans, and CYP17A1 inhibitors are being investigated as potential therapeutics for castration-resistant prostate cancer. The first X-ray crystal structures of this enzyme are now reported. Structures were obtained in the presence of the steroidal inhibitors abiraterone and TOK-001. The binding mode differs substantially from that predicted by homology models, and is of interest to structural biologists and those involved in developing improved inhibitors as potential therapeutics. Cytochrome P450 17A1 (also known as CYP17A1 and cytochrome P450c17) catalyses the biosynthesis of androgens in humans1. As prostate cancer cells proliferate in response to androgen steroids2,3, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer4, but drug development has been hampered by lack of information regarding the structure of CYP17A1. Here we report X-ray crystal structures of CYP17A1, which were obtained in the presence of either abiraterone, a first-in-class steroidal inhibitor recently approved by the US Food and Drug Administration for late-stage prostate cancer5, or TOK-001, an inhibitor that is currently undergoing clinical trials4,6. Both of these inhibitors bind the haem iron, forming a 60° angle above the haem plane and packing against the central I helix with the 3β-OH interacting with aspargine 202 in the F helix. Notably, this binding mode differs substantially from those that are predicted by homology models and from steroids in other cytochrome P450 enzymes with known structures, and some features of this binding mode are more similar to steroid receptors. Whereas the overall structure of CYP17A1 provides a rationale for understanding many mutations that are found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate a better understanding of the enzyme’s dual hydroxylase and lyase catalytic capabilities and assist in rational drug design. Specifically, structure-based design is expected to aid development of inhibitors that bind only CYP17A1 and solely inhibit its androgen-generating lyase activity to improve treatment of prostate and other hormone-responsive cancers.