Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

作者：Pippione Agnese C; Giraudo Alessandro; Bonanni Davide; Carnovale Irene M; Marini Elisabetta; Cena Clara; Costale Annalisa; Zonari Daniele; Pors Klaus; Sadiq Maria; Boschi Donatella; Oliaro Bosso Simonetta^*; Lolli Marco L^*

来源：European Journal of Medicinal Chemistry, 2017, 139: 936-946.

DOI：10.1016/j.ejmech.2017.08.046

• Aldo-keto reductase 1C3
• AKR1C3
• 17 beta-HSIDS
• Prostate cancer
• CRPC
• Bioisosterism
• Scaffold hopping
• Inhibitors

The aldo-keto reductase 10 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non -selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in pi-pi staking interaction with Trp227 (partial overlapping) and in a T-shape pi-pi staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.

• 出版日期2017-10-20