Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2

Inhibition of androgen biosynthesis
is clinically effective for treating androgen-responsive prostate
cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome
P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone
also causes hypertension, hypokalemia, and edema, likely due in part
to off-target inhibition of another steroidogenic cytochrome P450,
CYP21A2. Abiraterone analogs were designed based on structural evidence
that B-ring substituents may favorably interact with polar residues
in binding CYP17A1 and sterically clash with residues in the CYP21A2
active site. The best analogs increased selectivity of CYP17A1 inhibition
up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization
with CYP17A1 validated the intended new contacts with CYP17A1 active
site residues. Docking these analogs into CYP21A2 identified steric
clashes that likely underlie decreased binding and CYP21A2 inhibition.
Overall, these analogs may offer a clinical advantage in the form
of reduced side effects.