A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Aberrant androgen signaling drives prostate cancer (PCa).
• Therapeutic resistance occurs via androgen receptor (AR) overexpression or activation.
• Targeting AR for degradation is a potential therapeutic strategy.

Purpose of the Study:

• To evaluate IRC117539, a novel molecule targeting AR for proteasomal degradation.
• To assess the efficacy of AR degradation in preclinical models of prostate cancer.

Main Methods:

• Investigated IRC117539's mechanism of action on AR.
• Assessed IRC117539's effect on prostate cancer cell viability ex vivo.
• Evaluated IRC117539's efficacy in xenograft models compared to enzalutamide.

Main Results:

• IRC117539 induced AR sumoylation and ubiquitination, leading to proteasomal degradation.
• Ex vivo, IRC117539-mediated AR degradation reduced prostate cancer cell viability, including in androgen-insensitive cells.
• In vivo, IRC117539 showed potency similar to enzalutamide but was less effective than expected, due to weak proteasome inhibition.

Conclusions:

• Targeting AR for degradation is feasible and effective in preclinical prostate cancer models.
• Off-target effects, such as weak proteasome inhibition, can modulate in vivo drug efficacy.
• IRC117539 demonstrates potential for treating castration-resistant prostate cancer.