Multiple-targeting ligands for AKR1C3 enzyme and androgen receptor to target prostate cancer

The enzyme aldo-keto reductase 1C3 (AKR1C3) is considered an attractive target in Castration Resistant Prostate Cancer (CRPC) for its role in the biosynthesis of androgens (testosterone and DHT).1 At the same time, antagonists to Androgen Receptor (AR) as enzalutamide and darolutamide are used as anticancer drugs in CRPC patients. The two targets are compatible in terms of ligand accommodation as they are both able to interact with DHT as product and ligand, respectively. Our group already discovered new potent AKR1C3 inhibitors, where hydroxylated heterocycles were used to mimic acidic functions.1,2 We here propose new derivatives for both the hydroxybenzoisoxazole and the hydroxytriazole series, and move our attention on obtaining multiple ligands for both AKR1C3 and AR. To do this, we identified structural elements required for activity on AR and found some AKR1C3 inhibitors able to play AR antagonism activity; this represent a starting point for multiple-targeting ligand development applied to CRPC. The potency and dual action of new compounds are translated into citotoxicity against CRPC cellular models. In silico design, synthesis and biological activity on AKR1C3 enzyme of new compounds, as well as their capability to address AR, are here described.