Dihydrotanshinone as a Natural Product-Based CYP17A1 Lyase Inhibitor for Hyperandrogenic Disorders

Selective inhibition of CYP17A1 17,20-lyase activity is a major strategy for hyper-androgenic disorders, aiming to spare 17α-hydroxylase activity and avoid the side ef-fects of non-selective drugs like abiraterone. We investigated tanshinones isolated from Salvia miltiorrhiza (Danshen) using enzyme and cell-based assays. Dihydro-tanshinone (DT) was identified as the most potent and selective compound. At 10 µM, DT inhibited 17,20-lyase by 56.6% while sparing 17α-hydroxylase activity (>93% re-sidual). This corresponds to a lyase/hydroxylase selectivity index of 8.67, far superior to abiraterone (0.73). Furthermore, DT demonstrated lower off-target inhibition of CYP21A2 (14.9%) compared to abiraterone (29.8%). Molecular modeling suggested DT's efficacy stems from a unique, functionally disruptive binding pose rather than superior thermodynamic affinity. DT is a validated natural product lead, and its dual selectivity over both CYP17A1-hydroxylase and CYP21A2 establishes the tanshinone scaffold as a strong candidate for further medicinal chemistry optimization.