A Multivalent Peptoid Conjugate Modulates Androgen Receptor Transcriptional Activity to Inhibit Therapy-resistant...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Prostate cancer often develops resistance to androgen receptor (AR) pathway inhibitors.
• This resistance is driven by continued AR expression and function, leading to castration-resistant prostate cancer (CRPC).

Purpose of the Study:

• To develop and evaluate a novel multivalent peptoid conjugate (MPC) for inhibiting CRPC.
• To investigate the antitumor effects of MPC309, a specific ethisterone-based MPC, against resistant prostate cancer models.

Main Methods:

• Synthesis of MPC309, a trivalent ethisterone-conjugated peptoid oligomer with high AR binding affinity.
• Testing MPC309's antiproliferative effects on diverse enzalutamide-resistant prostate cancer models and mouse organoids.
• Analyzing cellular uptake via macropinocytosis and assessing the AR transcriptome, AR chromatin occupancy, and coregulatory protein interactions.
• Evaluating tumor suppression in xenograft studies compared to enzalutamide.

Main Results:

• MPC309 demonstrated potent antiproliferative activity across various resistant prostate cancer models, including those with AR variants and mutations.
• Cellular uptake occurred through cancer-selective macropinocytosis.
• MPC309 induced a unique AR gene expression profile, promoting differentiation and inhibiting cell division and metabolism.
• MPC309 significantly outperformed enzalutamide in suppressing tumor growth in vivo.

Conclusions:

• MPC309 is a promising new androgen receptor (AR) modulator for combating resistant prostate cancer.
• It effectively inhibits CRPC by inducing an antiproliferative AR gene expression program.
• Its selective uptake mechanism offers potential for targeted tumor therapy.