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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Identification of novel androgen receptor degrading agents to treat advanced prostate cancer
Hongxi Wu1, Jie Ren1, Lulu Zhao1
1Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Abstract:
Prostate cancer (PCa) is one of the most common malignancies affecting men worldwide. Androgen receptor (AR) has been a target of PCa treatment for nearly six decades. AR antagonists/degraders can effectively treat PCa caused by increased AR overexpression. However, all approved AR antagonists have similar chemical structures and exhibit the same mode of action on the protein. Although initially effective, resistance to these AR antagonists usually develops. Therefore, this calls for the identification of novel chemical structures of AR antagonists to overcome the resistance. Herein, we employed the synergetic combination of virtual and experimental screening to identify a flavonoid compound which not only effectively inhibits AR transcriptional activity, but also induces the degradation of the protein. Based on this compound, we designed and synthesized a series of derivatives. We discovered that the most potent compound 10e could effectively inhibit AR transcriptional activity, and possessed a profound ability to cause degradation of both full length- and ARv7 truncated forms of human AR. Notably, 10e efficiently inhibited the growth of ARv7 dependent prostate cancer cell-lines, which are completely resistant to all current anti-androgens. Compound 10e also showed strong antitumor activity in the LNCaP (androgen dependent prostate cancer cell line) in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists.
Insights
Researchers identified a novel flavonoid compound that inhibits androgen receptor (AR) activity and triggers its degradation. This new compound effectively targets prostate cancer (PCa) cells resistant to current therapies, offering a potential new treatment class.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Prostate cancer (PCa) is a prevalent malignancy in men globally.
- Androgen receptor (AR) is a key therapeutic target for PCa, but resistance to current antagonists is common.
- Existing AR antagonists share similar structures and mechanisms, necessitating novel approaches.
Purpose of the Study:
- To identify novel chemical structures targeting the androgen receptor (AR) to overcome treatment resistance in prostate cancer (PCa).
- To discover compounds that inhibit AR transcriptional activity and induce AR protein degradation.
- To develop a new class of AR antagonists for resistant PCa.
Main Methods:
- Employed a synergistic combination of virtual and experimental screening to identify a lead flavonoid compound.
- Synthesized a series of derivatives based on the identified flavonoid structure.
- Evaluated compound efficacy in inhibiting AR transcriptional activity, inducing AR degradation, and targeting AR-dependent cancer cells.
Main Results:
- Identified a potent flavonoid derivative (compound 10e) that inhibits AR transcriptional activity and induces degradation of both full-length and ARv7 forms.
- Compound 10e demonstrated efficacy against ARv7-dependent prostate cancer cell lines resistant to existing anti-androgens.
- Compound 10e exhibited significant antitumor activity in an in vivo xenograft model using LNCaP cells.
Conclusions:
- The novel flavonoid compound 10e represents a promising new class of AR antagonists.
- Compound 10e effectively targets AR and overcomes resistance mechanisms in prostate cancer.
- These findings provide a foundation for developing new treatments for advanced prostate cancer.
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