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.
摘要：
雄激素受体(AR)是治疗前列腺癌的一个有吸引力的靶点，考虑其在局限性和转移性前列腺癌的发展和进展中的作用。前列腺癌的高全球死亡率负担，尽管药物治疗如雄激素剥夺或AR拮抗剂治疗，强调了探索替代战略的必要性。一种策略涉及使用异双功能降解剂，也被称为蛋白水解靶向嵌合体，它们是抑制扩增或突变靶标的新型小分子疗法。这里,该研究报告了一种新型的基于小脑的AR降解剂，UBX-390，并证明其优于已建立的AR降解剂的活性，例如ARV-110或ARCC-4，在短期和长期治疗条件下的前列腺癌细胞中。UBX-390抑制AR的染色质结合和基因表达，并在治疗抗性前列腺癌患者中显示出AR突变体降解的实质性功效。UBX-390是一种优化的AR降解剂，具有治疗去势抵抗性前列腺癌的巨大潜力。
