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
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