MON-179 Renal and Hepatic Effects of Androgen Receptor Downregulation by PROTAC ARV-110 in a Mouse Model of Polycystic Ovary Syndrome

Abstract Disclosure: J. Basnet: None. S. Rezq: None. A.M. Huffman: None. L.L. Yanes Cardozo: None. D.G. Romero: None. Background: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women, which is characterized by obesity, insulin resistance, and renal injury. Hyperandrogenism, a hallmark of PCOS, drives metabolic dysfunction via the androgen receptor (AR). While AR blockers may alleviate PCOS complications, their hepatotoxicity limits their use, highlighting the need for safer therapeutic options. ARV-110, a novel AR PROteolysis Targeting Chimera (PROTAC) degrader, has shown efficacy in prostate cancer but remains untested in PCOS. Therefore, we hypothesize that ARV-110 will dose-dependently reduce androgen-induced metabolic and renal dysfunctions without causing hepatotoxicity in a hyperandrogenemic mouse model of PCOS. Methods: Three-week-old female (C57BL/6N) mice were implanted with Silastic tubes containing dihydrotestosterone (DHT, 8 mg, s.c., 90 days) or control (CON) (n=6/grp). Four weeks post-DHT administration, mice were treated s.c. with ARV-110 at low (ARV-L, 1 mg/kg/day) or high (ARV-H, 10 mg/kg/day) doses, or vehicle (VEH) for 8 wks. Body weight (BW), kidney and liver weights, body composition (by EchoMRI), fasting glucose (FG), and oral glucose tolerance (OGTT) were assessed. Renal injury markers (UACR, KIM-1, NGAL) and liver injury markers (AST, ALT, LDH) were measured in urine and serum, respectively. Liver proteome was analyzed with VolcaNoseR and BioVenn. Data were analyzed by 2-way ANOVA. Results: DHT-VEH mice showed significant (p<0.05) increases in BW (1.14-fold), fat mass (2-fold), lean mass (1.09-fold), FG (1.29-fold), and impaired glucose tolerance (OGTT, AUC 1.47-fold) compared to CON-VEH. Both ARV-L and ARV-H treatments in DHT mice reduced BW, fat mass, FG, and OGTT without affecting lean mass. DHT-VEH-treated mice had increased kidney weight, UACR, and NGAL levels which were attenuated by ARV-110 in a dose-dependent manner. In the liver, ARV-L had no effect on DHT-mediated increases in liver weight, while ARV-H further increased it. Similarly, ALT, AST, and LDH levels were comparable between VEH- and ARV-L-treated mice, but ARV-H significantly elevated these markers, suggesting hepatotoxicity. Liver proteomics identified 217 differentially expressed proteins (DEPs) in DHT-VEH vs. CON-VEH mice. Compared to DHT-VEH mice, ARV-L treatment induced 76 DEPs, while ARV-H caused a substantially higher number of 681 DEPs. Conclusion and significance: Our findings show that targeting AR with ARV-110 alleviates DHT-induced obesity, glucose intolerance, and kidney hypertrophy and injury in a dose-dependent manner. However, liver injury markers and proteomics reveal minimal liver effects with ARV-L, while ARV-H causes severe hepatotoxicity. These results suggest that AR PROTAC degraders could be a promising approach for managing metabolic and renal complications in PCOS, with careful dosing to avoid adverse effects. Presentation: Monday, July 14, 2025