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Androgen receptor antagonists produced by Streptomyces overcome resistance to enzalutamide


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.

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Work on new AR antagonists at Keio University was funded by a grant program for bioinformatics research and development of the Japan Science and Technology Agency, grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT KAKENHI Grant Number JP23102006 and JSPS KAKENHI Grant Number JP15H03116 to MI).

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M.I. supervised this review article. T.F, S.S and E.T. wrote this review article.

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Correspondence to Masaya Imoto.

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Imoto, M., Fujimaki, T., Saito, S. et al. Androgen receptor antagonists produced by Streptomyces overcome resistance to enzalutamide. J Antibiot 74, 706–716 (2021).

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