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ARD-69 is a PROTAC degrader based on the E3 ubiquitin ligase VHL and targeting the androgen receptor, which can induce androgen receptor (AR) protein degradation in AR-positive prostate cancer cells. ARD-69 inhibits AR-regulated gene expression, binds to the AR ligand binding domain at one end and binds to VHL at the other end, prompting AR to be recruited to the E3 ubiquitin ligase complex, triggering proteasome degradation, thereby inhibiting AR signaling pathways and downstream gene expression (such as PSA, TMPRSS2). ARD-69 can be used to study the treatment of castration-resistant prostate cancer (mCRPC)[1][2][3]. | [in vivo]
ARD-69 (50 mg/kg; intraperitoneal injection; single dose) significantly reduces AR and PSA protein levels in tumor tissues in a VCaP xenograft tumor model in severe combined immunodeficient (SCID) mice, with the effect lasting for at least 48 hours[1]. | Animal Model: | Female severe combined immunodeficient (SCID) mice with VCaP xenograft tumors[1] | | Dosage: | 50 mg/kg, dissolved in an appropriate solvent (e.g., DMSO/saline formulation) | | Administration: | Intraperitoneal (IP) injection, single dose | | Result: |
Significantly reduced androgen receptor (AR) and prostate-specific antigen (PSA) protein levels in tumor tissues, with effects detectable as early as 3 hours post-treatment and persisting for at least 48 hours.
Dose-dependently decreased in AR and PSA expression relative to the loading control GAPDH, indicating sustained pharmacodynamic activity in vivo. |
| [References]
[1] Han X, et al. Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer. J Med Chem. 2019 Jan 10. DOI:10.1021/acs.jmedchem.8b01631
[2] Du W. Advances in AR-targeting chimeras: a case study of proteolysis-targeting chimeras from bench to bedside. Future Med Chem. 2022 Oct;14(20):1471-1489. DOI:10.4155/fmc-2022-0147
[3] Xiang, et al. Recent advances in targeting the androgen receptor with PROTACS. 2022 Medicinal Chemistry Reviews (2022). |
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