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

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. Aldo-keto reductase 1C3 (AKR1C3) is known to be a cancer biomarker correlated to androgen synthesis, and causes drug resistance by direct action on chemotherapeutics and by stabilizing AR splice variant 7 (ARv7). While selective inhibitors against AKR1C3 are developed, the ARv7 is thought to be undruggable. Here, the authors develop an AKR1C3-ARv7 dual PROTAC degrader based on a selective inhibitor against AKR1C3, showing the potential for degradation of AKR1C3 and ARv7 simultaneously.