Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 94158, United States.
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94158, United States.
Eur J Med Chem. 2023 Mar 5;249:115110. doi: 10.1016/j.ejmech.2023.115110. Epub 2023 Jan 14.
Clinical responses to second generation androgen signaling inhibitors (e.g., enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) are variable and transient, and are associated with dose limiting toxicities, including rare but severe CNS effects. We hypothesized that changes to iron metabolism coincident with more advanced disease might be leveraged for tumor-selective delivery of antiandrogen therapy. Using the recently described chemical probes SiRhoNox and F-TRX in mCRPC models, we found elevated Fe to be a common feature of mCRPC in vitro and in vivo. We next synthesized ferrous-iron activatable drug conjugates of second and third-generation antiandrogens and found these conjugates possessed comparable or enhanced antiproliferative activity across mCRPC cell line models. Mouse pharmacokinetic studies showed that these prototype antiandrogen conjugates are stable in vivo and limited exposure to conjugate or free antiandrogen in the brain. Our results reveal elevated Fe to be a feature of mCRPC that might be leveraged to improve the tolerability and efficacy of antiandrogen therapy.
在转移性去势抵抗性前列腺癌（mCRPC）中，第二代雄激素信号抑制剂（如恩扎鲁胺）的临床反应是多变且短暂的，并与剂量限制毒性相关，包括罕见但严重的中枢神经系统影响。我们假设，与更晚期疾病同时发生的铁代谢变化可能被用于雄激素治疗的肿瘤选择性递送。我们使用最近描述的 SiRhoNox 和 F-TRX 化学探针在 mCRPC 模型中发现，体外和体内 mCRPC 中 Fe 升高是一个常见特征。接下来，我们合成了第二代和第三代抗雄激素的亚铁离子激活药物偶联物，并发现这些偶联物在 mCRPC 细胞系模型中具有相当或增强的抗增殖活性。小鼠药代动力学研究表明，这些原型抗雄激素偶联物在体内稳定，脑内偶联物或游离抗雄激素的暴露有限。我们的结果表明，Fe 升高是 mCRPC 的一个特征，可能被利用来提高抗雄激素治疗的耐受性和疗效。
