2. Academic Validation
  3. Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader

Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader

  • Commun Chem. 2024 Apr 29;7(1):95. doi: 10.1038/s42004-024-01177-4.
Angelica V Carmona # 1,  Shirisha Jonnalagadda # 1,  Alfie M Case 1,  Krishnaiah Maddeboina 1,  Sravan K Jonnalagadda 1,  Louise F Dow 1,  Ling Duan 2,  Trevor M Penning 2,  Paul C Trippier 3 4 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA.
  • 2 Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA. paul.trippier@unmc.edu.
  • 4 Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68106, USA. paul.trippier@unmc.edu.
  • 5 UNMC Center for Drug Design and Innovation, University of Nebraska Medical Center, Omaha, NE, 68106, USA. paul.trippier@unmc.edu.
  • # Contributed equally.
PMID: 38684887 DOI: 10.1038/s42004-024-01177-4
Abstract

Aldo-keto reductase 1C3 (AKR1C3) is a protein upregulated in prostate Cancer, hematological malignancies, and other cancers where it contributes to proliferation and chemotherapeutic resistance. Androgen Receptor splice variant 7 (ARv7) is the most common mutation of the AR receptor that confers resistance to clinical Androgen Receptor signalling inhibitors in castration-resistant prostate Cancer. AKR1C3 interacts with ARv7 promoting stabilization. Herein we report the discovery of the first-in-class AKR1C3 Proteolysis-Targeting Chimera (PROTAC) degrader. This first-generation degrader potently reduced AKR1C3 expression in 22Rv1 prostate Cancer cells with a half-maximal degradation concentration (DC50) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was observed with a DC50 = 70 nM, along with degradation of the AKR1C3 isoforms AKR1C1 and AKR1C2 to a lesser extent. This compound represents a highly useful chemical tool and a promising strategy for prostate Cancer intervention.

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