The structural basis of aldo-keto reductase 1C3 inhibition by 17α-picolyl and 17(<i>E</i>)-picolinylidene androstane derivatives.

ABSTRACT: Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17α-picolyl androstane with a C3-oxime modification, was determined at 1.7 Å resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17α-picolyl or 17(E)-picolinylidene derivatives depends on interactions between the C3 modification and the NADP⁺ cofactor, while the C17α-picolyl or C17-picoli

SUBMITTER: Plavsa-Puz JJ 

PROVIDER: S-EPMC12412325 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature