Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader
Angelica V. Carmona, Shirisha Jonnalagadda, Alfie M. Case, Maddeboina Krishnaiah, Sravan K. Jonnalagadda, Louise F. Dow, Ling Duan, T.M. Penning, Paul C. Trippier
Abstract
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 (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.