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

Autor: Carmona AV; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA., Jonnalagadda S; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA., Case AM; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA., Maddeboina K; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA., Jonnalagadda SK; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA., Dow LF; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA., Duan L; Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA., Penning TM; Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA., Trippier PC; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA. paul.trippier@unmc.edu.; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68106, USA. paul.trippier@unmc.edu.; UNMC Center for Drug Design and Innovation, University of Nebraska Medical Center, Omaha, NE, 68106, USA. paul.trippier@unmc.edu.
Jazyk: angličtina
Zdroj: Communications chemistry [Commun Chem] 2024 Apr 29; Vol. 7 (1), pp. 95. Date of Electronic Publication: 2024 Apr 29.
DOI: 10.1038/s42004-024-01177-4
Abstrakt: 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 (DC 50 ) of 52 nM. Gratifyingly, concomitant degradation of ARv7 was observed with a DC 50  = 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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