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Updated: Jun 22, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
UBX-390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer
Soohyun Lee1,2, Hwa-Ryeon Kim2, Yaejin Woo1
1Ubix Therapeutics, Seoul, 05836, Republic of Korea.
Abstract:
The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic prostate cancer. The high global mortality burden of prostate cancer, despite medical treatments such as androgen deprivation or AR antagonist therapy, highlights the need to explore alternative strategies. One strategy involves the use of heterobifunctional degraders, also known as proteolysis-targeting chimeras, which are novel small-molecule therapeutics that inhibit amplified or mutated targets. Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.
Insights
A novel cereblon-based androgen receptor (AR) degrader, UBX-390, shows superior efficacy in degrading AR and its mutants. This new therapeutic holds significant potential for treating castration-resistant prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer progression is driven by the androgen receptor (AR).
- Existing treatments like androgen deprivation therapy and AR antagonists have limitations, necessitating novel therapeutic strategies.
- Heterobifunctional degraders, or proteolysis-targeting chimeras (PROTACs), offer a new approach to target amplified or mutated proteins.
Purpose of the Study:
- To develop and evaluate a novel cereblon-based AR degrader, UBX-390.
- To compare the efficacy of UBX-390 against existing AR degraders in prostate cancer models.
- To assess UBX-390's potential in treating treatment-resistant prostate cancer.
Main Methods:
- Development of a novel cereblon-based heterobifunctional degrader (UBX-390).
- In vitro testing of UBX-390 in prostate cancer cell lines under short- and long-term treatment.
- Assessment of AR chromatin binding and gene expression suppression.
- Evaluation of AR mutant degradation in patient-derived models.
Main Results:
- UBX-390 demonstrated superior activity compared to established AR degraders (ARV-110, ARCC-4) in prostate cancer cells.
- UBX-390 effectively suppressed AR chromatin binding and gene expression.
- Significant efficacy was observed in the degradation of AR mutants from patients with treatment-resistant prostate cancer.
Conclusions:
- UBX-390 is an optimized AR degrader with potent activity.
- UBX-390 shows remarkable potential for treating castration-resistant prostate cancer, including cases with AR mutations.
