1. New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold.
- Author
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Pippione AC, Kilic-Kurt Z, Kovachka S, Sainas S, Rolando B, Denasio E, Pors K, Adinolfi S, Zonari D, Bagnati R, Lolli ML, Spyrakis F, Oliaro-Bosso S, and Boschi D
- Subjects
- Androgens, Humans, Male, Aldo-Keto Reductase Family 1 Member C3 antagonists & inhibitors, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
The aldo-keto reductase 1C3 (AKR1C3) enzyme is considered an attractive target in Castration Resistant Prostate Cancer (CRPC) because of its role in the biosynthesis of androgens. Flufenamic acid, a non-selective AKR1C3 inhibitor, has previously been subjected to bioisosteric modulation to give rise to a series of compounds with the hydroxytriazole core. In this work, the hit compound of the previous series has been modulated further, and new, more potent, and selective derivatives have been obtained. The poor solubility of the most active compound (cpd 5) has been improved by substituting the triazole core with an isoxazole heteronucleous, with similar enzymatic activity being retained. Potent AKR1C3 inhibition is translated into antiproliferative effects against the 22RV1 CRPC cellular model, and the in-silico design, synthesis and biological activity of new compounds are described herein. Compounds have also been assayed in combination with two approved antitumor drugs, abiraterone and enzalutamide., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
- Published
- 2022
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