2. Academic Validation
  3. New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold

New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold

  • Eur J Med Chem. 2022 Jul 5;237:114366. doi: 10.1016/j.ejmech.2022.114366.
Agnese Chiara Pippione 1,  Zühal Kilic-Kurt 2,  Sandra Kovachka 1,  Stefano Sainas 1,  Barbara Rolando 1,  Enrica Denasio 3,  Klaus Pors 3,  Salvatore Adinolfi 1,  Daniele Zonari 1,  Renzo Bagnati 4,  Marco Lucio Lolli 1,  Francesca Spyrakis 5,  Simonetta Oliaro-Bosso 6,  Donatella Boschi 7
Affiliations

Affiliations

  • 1 Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy.
  • 2 Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey.
  • 3 Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, West Yorkshire, BD7 1DP, UK.
  • 4 Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via Mario Negri 2, 20156, Milan, Italy.
  • 5 Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy. Electronic address: [email protected].
  • 6 Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy. Electronic address: [email protected].
  • 7 Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy. Electronic address: [email protected].
PMID: 35447434 DOI: 10.1016/j.ejmech.2022.114366
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.

Figures
Products