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

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.

• Authors: Angelica V Carmona, Shirisha Jonnalagadda, Alfie M Case, Krishnaiah Maddeboina, Sravan K Jonnalagadda, Louise F Dow, Ling Duan, Trevor M Penning, Paul C Trippier
• Journal: Communications chemistry (Commun Chem) Vol. 7 Issue 1 Pg. 95 (Apr 29 2024) ISSN: 2399-3669 [Electronic] England
• PMID: 38684887 (Publication Type: Journal Article)
• Copyright: © 2024. The Author(s).