Prostate cancer (PC) is a leading cause of cancer-related death in men in Western countries. Androgen receptor (AR) signaling is a major driver of PC; therefore, androgen deprivation by medical and surgical castration is the standard treatment for patients with PC. However, over time, most patients will progress to metastatic castration-resistant PC. Enzalutamide is the only AR antagonist approved by the Food and Drug Administration for the treatment of metastatic castration-resistant PC. However, resistance to enzalutamide also develops in most patients with castration-resistant PC. Thus, there is an urgent need to develop new AR antagonists with new structures. For this purpose, we conducted both in silico and natural product screenings. From the in silico screening, we obtained T5853872 and more potent compound, STK765173. From the natural product screening, the novel compound arabilin was isolated from Streptomyces sp. MK756-CF1. Unlike STK765173, arabilin could overcome resistance to enzalutamide. Furthermore, we also extracted a novel compound, antarlide A, and its geometric isomers from Streptomyces sp. BB47. Antarlides A–F have novel 22-membered-ring macrocyclic structures, while antarlides G and H have 20-membered-ring structures. Both antarlides B and G showed potent AR antagonist activity in prostate cancer cells and could overcome resistance to enzalutamide.

前列腺癌 (PC) 是西方国家男性癌症相关死亡的主要原因。雄激素受体 (AR) 信号是 PC 的主要驱动因素；因此，通过药物和手术去势去除雄激素是 PC 患者的标准治疗方法。然而，随着时间的推移，大多数患者会发展为转移性去势抵抗性 PC。Enzalutamide 是唯一被美国食品和药物管理局批准用于治疗转移性去势抵抗性 PC 的 AR 拮抗剂。然而，大多数去势抵抗性 PC 患者也会对恩杂鲁胺产生耐药性。因此，迫切需要开发具有新结构的新型AR拮抗剂。为此，我们进行了计算机和天然产物筛选。通过计算机筛选，我们获得了 T5853872 和更有效的化合物 STK765173。链霉菌属 MK756-CF1。与 STK765173 不同，arabilin 可以克服对恩杂鲁胺的耐药性。此外，我们还从链霉菌中提取了一种新化合物 antarlide A 及其几何异构体。BB47。Antarlides A–F 具有新颖的 22 元环大环结构，而 Antarlides G 和 H 具有 20 元环结构。antarlides B 和 G 都在前列腺癌细胞中显示出强大的 AR 拮抗剂活性，并且可以克服对恩杂鲁胺的耐药性。