A Targeted Bivalent Androgen Receptor Binding Compound for Prostate Cancer Therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Prostate cancer (PCa) treatment faces challenges due to drug resistance, often involving androgen receptor (AR) mutations.
• Classical androgen withdrawal or blockade therapies can fail as PCa progresses.

Purpose of the Study:

• To develop a novel AR-directed therapeutic agent to overcome treatment resistance in PCa.
• To create bivalent compounds that bind with high affinity to the AR within cancer cells.

Main Methods:

• Utilized molecular modeling and synthetic chemistry to design and synthesize novel compounds.
• Conjugated 5α-dihydrotestosterone (DHT) to AF-2 motif sequence peptides using spacer linkers.
• Evaluated in vitro binding affinity and cellular uptake of the bivalent compounds.

Main Results:

• Synthesized bivalent compounds demonstrated high-affinity binding to the AR in vitro.
• Altering the AF-2 peptide composition influenced the binding affinity to the AR.
• Many bivalent compounds successfully penetrated the plasma membrane and competed with endogenous androgens.

Conclusions:

• Novel bivalent AR-directed compounds show promise for overcoming PCa treatment resistance.
• These compounds effectively bind to and compete with androgens, offering a potential new therapeutic strategy.