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.

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

Chiara Vigato
First
;
Agnese Chiara Pippione;Stefano Sainas;Iole Mannella;Barbara Rolando;Francesca Spyrakis;Simonetta Oliaro-Bosso;Marco Lucio Lolli;Donatella Boschi
Last
2023-01-01

Abstract

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.
2023
Merck Young Chemist’s Symposium 2023
Rimini (Italy)
13th -15th November 2023
Proceedings of the Merck Young Chemist’s Symposium 2023, XXII Ed.
197
197
Chiara Vigato, Agnese Chiara Pippione, Stefano Sainas, Iole Mannella, Laura Bertarini, Sandra Kovachka, Barbara Rolando, Osman Asghar Mirza, Karla Fry...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1949674
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