New Hydroxybenzoazole Inhibitors of Aldo-Keto Reductase 1C3 (AKR1C3): Disclosure of SAR Investigation to Target Prostate Cancer

Human Aldo-keto reductase 1C3 (AKR1C3) plays a pivotal role in androgen biosynthesis and has been deeply studied as a potential therapeutical target in several types of cancer. One of the most investigated applications of AKR1C3 inhibitors is their use in Castration-Resistant Prostate Cancer (CRPC) treatment, as well as their ability to prevent drug resistance. At the present, no selective AKR1C3-targeted agent has been approved for clinical use, therefore interest in advancing optimized AKR1C3 inhibitors has been increased during the last years 1. Recently, our research group designed new hydroxybenzoisoxazole scaffold-based AKR1C3 inhibitors thanks to the application of a conformational restriction of the benzoic acid moiety of the non-selective AKR1C3 inhibitor flufenamic acid. The most potent and selective compound (1) binding mode was determined through X-ray crystallography (figure 1) 2. Here we disclose a new series of hydroxybenzoazole derivatives in which the B-ring was modulated through the introduction of further substituents. This SAR investigation aims in exploring additional interactions within subpocket SP1 of AKR1C3 active site. In silico design, synthesis, and in vitro biological evaluation (enzymatic inhibition and cellular antiproliferative activity) of the new series of AKR1C3 inhibitors are here described and discussed. 1. Liu, Y. et al. Overview of AKR1C3: inhibitor achievements and disease insights. J. Med. Chem. 2020, 63, 11305–11329. 2. Pippione, A. C. et al. Potent and selective Aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid. Eur. J. Med. Chem. 2018, 150, 930-945.