Abstract 1620: Identification of a molecular degrader targeting the AR-V7 splice variant

Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effective therapy has been demonstrated for patients with metastatic prostate cancer bearing the AR-V7 signature. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bound to AR-V7. One such molecule, CL-AR-100, directly bound to AR-V7 and moreover, induced proteasomal-mediated targeted protein degradation of both AR-V7 and AR-FL. This compound did not affect the expression of other structurally related ligand-activated nuclear receptors. In prostate cancer cell lines expressing AR-FL, CL-AR-100 induced a gene expression profile similar to cells treated with Enza including a marked reduction in KLK3 (PSA) expression. Moreover, CL-AR-200 inhibited the growth of 22RV1 cells (IC50=0.3uM), a cell line that predominantly expresses AR-V7. In contrast, the compound did not affect the growth of a wide variety of non-tumorigenic cells, non-prostate tumor cell lines or PC3 cells, a prostate cell line that exhibits AR-independent cell growth. These results thereby identify a small molecule molecular degrader that can specifically induce the targeted protein degradation of the AR-V7 splice variant. Given the strong association of this isoform with treatment resistance, this approach would appear to provide an attractive strategy for patients with metastatic castration resistant prostate cancer. Citation Format: Yuan Liu, Bo Lin, Mads B. Larsen, Irene Alfaras, Jason R. Kennerdell, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Identification of a molecular degrader targeting the AR-V7 splice variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1620.