Discovery of an Aldo-Keto Reductase 1C3 (AKR1C3) Degrader

Authors

Angelica V. Carmona, University of Nebraska Medical Center
Shirisha Jonnalagadda, University of Nebraska Medical Center
Alfie M. Case, University of Nebraska Medical CenterFollow
Krishnaiah Maddeboina, University of Nebraska Medical Center
Sravan K. Jonnalagadda, University of Nebraska Medical CenterFollow
Louise F. Dow, University of Nebraska Medical CenterFollow
Ling Duan, University of Pennsylvania
Trevor M. Penning, University of Pennsylvania
Paul C. Trippier, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Communications Chemistry

Publication Date

2024

Volume

7

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.

DOI Link

10.1038/s42004-024-01177-4

ISSN

2399-3669

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Carmona, Angelica V.; Jonnalagadda, Shirisha; Case, Alfie M.; Maddeboina, Krishnaiah; Jonnalagadda, Sravan K.; Dow, Louise F.; Duan, Ling; Penning, Trevor M.; and Trippier, Paul C., "Discovery of an Aldo-Keto Reductase 1C3 (AKR1C3) Degrader" (2024). Journal Articles: Pharmaceutical Sciences. 45.
https://digitalcommons.unmc.edu/cop_pharmsci_articles/45