A new generation of AKR1C3 inhibitors on the horizon: the 3- hydroxybenzazole approach to target prostate cancer

Aldo-Keto Reductase 1C3 (AKR1C3) has a key role in androgen biosynthesis, thus an increasing number of studies have focused on AKR1C3 inhibitors for their potential application in treating Castration-Resistant Prostate Cancer and preventing drug resistance [1]. Since flufenamic acid (FLU, Figure 1) is known to inhibit AKR1C3 in weak and non-selective mode, we employed in recent years a conformational restriction strategy on FLU anthranilic core to afford a bioisosteric 3-hydroxybenzoisoxazole-scaffold based series of compounds [2]. Thanks to the binding pose of the lead compound 1 inside AKR1C3 enzyme, determined through X-ray crystallography [2], we designed the next optimized round of hydroxybenzazole derivatives, where the B-ring is modulated by further substituents with the purpose of increasing potency and retaining selectivity through a deeper exploration of AKR1C3 binding pocket (Figure 1). In silico design, synthesis, in vitro biological evaluation (enzymatic and cellular assays) and X-ray structures of the new AKR1C3 inhibitors are here described and discussed.