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Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate
Pratap Singh1, Gurulingappa Hallur, Ravi K Anchoori
1Chemical and Biomolecular Engineering, Whiting School of Engineering, Baltimore, Maryland, USA.
Background:
The standard hormonal therapy with currently available antiandrogens and the leutinizing hormone releasing hormone (LHRH) analogs is not effective in the hormone-refractory stage of prostate cancer due to changes in androgen receptor (AR) signaling axis. In this refractory stage, AR continues to play a significant role in the growth of cancer cells even though the cancer cells are no longer dependent on the level of circulating androgens.
Methods:
A series of 11beta-Delta(9)-19 nortestosterone compounds were designed through structure-based rationale and tested for their binding affinity against AR and glucocorticoid receptor (GR) using fluorescence polarization assays, their agonistic ability to induce AR dependent transcription using PSA-driven report gene assays, and their growth inhibitory affects against a series of AR positive (LAPC4, LNCap, and CWR22R) and negative human prostate cancer cell lines (PC3) using MTT cell proliferation assays.
Results:
This study proposes the design of novel bifunctional antiandrogens based on the conjugation of 11beta and/or 7alpha-Delta(9)-19 nortestosterone class of steroidal compounds to the synthetic ligand for FK506-binding proteins. As a critical step towards the development of bifunctional antiandrogens, highly potent and AR-specific lead compounds were identified using in vitro data. The lead compounds identified in this study possessed low binding affinity for GR, indicating the absence of undesirable antiglucocorticoid activity.
Conclusions:
The results of this study validate our drug discovery rationale based on the structural biology of AR and pave the pay for future development of bifunctional compounds in order to block AR function in hormone refractory stage of prostate cancer.
Insights
Researchers developed novel bifunctional antiandrogens targeting the androgen receptor (AR) for hormone-refractory prostate cancer. These compounds show potent AR specificity and low glucocorticoid receptor (GR) activity, offering a new therapeutic strategy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Standard hormonal therapies fail in hormone-refractory prostate cancer due to altered androgen receptor (AR) signaling.
- AR remains crucial for cancer growth even without circulating androgens.
Purpose of the Study:
- To design novel bifunctional antiandrogens targeting the AR signaling axis.
- To develop compounds effective in the hormone-refractory stage of prostate cancer.
Main Methods:
- Structure-based design of 11beta-Delta(9)-19 nortestosterone derivatives.
- In vitro assays for AR/GR binding affinity, AR-dependent transcription, and cell proliferation.
- Testing against AR-positive and AR-negative prostate cancer cell lines.
Main Results:
- Identified potent and AR-specific lead compounds.
- Conjugated steroidal compounds to FK506-binding protein ligands for bifunctional activity.
- Lead compounds exhibited low binding affinity for GR, indicating minimal antiglucocorticoid effects.
Conclusions:
- Validated a drug discovery rationale based on AR structural biology.
- Paved the way for developing bifunctional compounds to block AR function in hormone-refractory prostate cancer.
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