Human aldo-keto reductase family 1 member C3 (AKR1C3) has been deeply studied as potential drug target in several types of cancer and an increasing number of studies have investigated AKR1C3 inhibitors1. One of the most investigated application is their use in prevention and treatment of Castration Resistance Prostate Cancer (CRPC), as well as their ability to overcome the drug resistance1. In last years, our research group developed a series of hydroxybenzoisoxazole AKR1C3 inhibitors through the application of a bioisosteric scaffold hopping approach to the non-selective AKR1C3 inhibitor flufenamic acid2. The best compound binding mode was determined by X-ray crystallography. Here we present improvement of the first series, obtained modulating the B-ring and introducing an additional phenyl (D-ring), in order to explore interactions within the subpocket SP1 of the AKR1C3 active site (Figure 1). Substituents on D ring were introduced in order to explore the role of H-bond donor/acceptor groups. In silico design, synthesis and biological activity (enzymatic and cellular assays) of new compounds are here described

New inhibitors of Aldo-Keto Reductase 1C3 (AKR1C3) based on benzoisoxazole scaffold and their potential application in cancer

Mannella Iole;Vigato Chiara;Pippione Agnese Chiara;Sainas Stefano;Oliaro Bosso Simonetta;Rolando, Barbara;Kovachka Sandra;Spyrakis Francesca;Boschi Donatella;Lolli. Marco Lucio
2021

Abstract

Human aldo-keto reductase family 1 member C3 (AKR1C3) has been deeply studied as potential drug target in several types of cancer and an increasing number of studies have investigated AKR1C3 inhibitors1. One of the most investigated application is their use in prevention and treatment of Castration Resistance Prostate Cancer (CRPC), as well as their ability to overcome the drug resistance1. In last years, our research group developed a series of hydroxybenzoisoxazole AKR1C3 inhibitors through the application of a bioisosteric scaffold hopping approach to the non-selective AKR1C3 inhibitor flufenamic acid2. The best compound binding mode was determined by X-ray crystallography. Here we present improvement of the first series, obtained modulating the B-ring and introducing an additional phenyl (D-ring), in order to explore interactions within the subpocket SP1 of the AKR1C3 active site (Figure 1). Substituents on D ring were introduced in order to explore the role of H-bond donor/acceptor groups. In silico design, synthesis and biological activity (enzymatic and cellular assays) of new compounds are here described
13th Young Medicinal Chemist's Symposium-Nuove Prospettive in Chimica Farmaceutica,
Virtual Event
26 - 29 Aprile, 2021
13th Young Medicinal Chemist's Symposium-Nuove Prospettive in Chimica Farmaceutica
109
109
Mannella, Iole, Vigato, Chiara, Pasha, Rabia; Pippione Agnese Chiara, Sainas, Stefano, Oliaro Bosso Simonetta; Rolando, Barbara; Kovachka, Sandra, Spyrakis, Francesca; Boschi, Donatella, Lolli. Marco Lucio
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1852078
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