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Updated: Oct 27, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Androgen receptor antagonists produced by Streptomyces overcome resistance to enzalutamide
Masaya Imoto1, Takahiro Fujimaki2, Shun Saito3
1Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan. m.imoto.xz@juntendo.ac.jp.
Abstract:
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.
Insights
New androgen receptor (AR) antagonists were discovered to combat advanced prostate cancer (PC). These compounds, including arabilin and antarlides, show promise in overcoming resistance to current treatments like enzalutamide.
Area of Science:
- Oncology
- Medicinal Chemistry
- Natural Products
Background:
- Prostate cancer (PC) is a significant cause of cancer-related mortality in men.
- Androgen receptor (AR) signaling drives PC progression, making androgen deprivation therapy (ADT) a standard treatment.
- Resistance to ADT and AR antagonists like enzalutamide necessitates the development of novel therapeutic agents.
Purpose of the Study:
- To identify novel androgen receptor (AR) antagonists with new structures.
- To overcome acquired resistance to enzalutamide in metastatic castration-resistant prostate cancer (mCRPC).
Main Methods:
- In silico screening to identify potential AR antagonists.
- Natural product screening of microbial isolates for novel compounds.
- Evaluation of AR antagonist activity and efficacy in overcoming enzalutamide resistance in prostate cancer cells.
Main Results:
- In silico screening yielded compounds T5853872 and STK765173.
- Arabilin, isolated from Streptomyces sp. MK756-CF1, demonstrated activity against enzalutamide-resistant prostate cancer.
- Novel compounds antarlides A-H were isolated from Streptomyces sp. BB47, with antarlides B and G showing potent AR antagonist activity and overcoming enzalutamide resistance.
Conclusions:
- Novel AR antagonists, arabilin and antarlides, have been identified.
- These compounds exhibit potent anti-prostate cancer activity.
- Arabilin and antarlides B/G represent promising candidates for overcoming enzalutamide resistance in advanced prostate cancer.
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