Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer
© 2023, Wu, Zhang, Zhang et al..
In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
eLife - 12(2023) vom: 19. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wu, Meng [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.02.2023 Date Revised 22.03.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.7554/eLife.70700 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM351674144 |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023, Wu, Zhang, Zhang et al. | ||
| 520 | |a In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment | ||
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| 650 | 4 | |a antiandrogen | |
| 650 | 4 | |a cancer biology | |
| 650 | 4 | |a castration-resistant prostate cancer | |
| 650 | 4 | |a degrader | |
| 650 | 4 | |a enzalutamide resistance | |
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| 700 | 1 | |a Zhang, Rongyu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zixiong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chenfan |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Yongli |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Haoran |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Fangjiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ruoying |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaoyu |e verfasserin |4 aut | |
| 700 | 1 | |a Cen, Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Jinming |e verfasserin |4 aut | |
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