Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Castration-resistant prostate cancer (CRPC) poses significant treatment challenges due to clinical resistance mechanisms.
• Resistance is often driven by androgen receptor (AR) alterations, including mutations, overexpression, and splice variants (ARVs), limiting the efficacy of current therapies like second-generation antiandrogens (SGAs).

Purpose of the Study:

• To identify and characterize novel therapeutic agents capable of overcoming SGA resistance in CRPC.
• To evaluate the potential of a bifunctional small molecule, Z15, as a dual AR antagonist and degrader for advanced prostate cancer treatment.

Main Methods:

• Biochemical assays to determine Z15's interaction with the AR ligand-binding domain (LBD) and activation function-1 (AF1) region.
• In vitro and in vivo studies to assess Z15's effects on AR transcriptional activity, mRNA and protein levels, and downstream targets.
• Evaluation of Z15's efficacy in preclinical models of CRPC exhibiting resistance to SGAs.

Main Results:

• Z15 was identified as a bifunctional molecule exhibiting both AR antagonism and selective AR degradation via the proteasome pathway.
• Z15 effectively suppressed the transcriptional activity of wild-type AR, AR mutants, and ARVs.
• The compound downregulated AR downstream target genes, demonstrating efficacy against AR LBD mutations, amplification, and ARV-induced SGA resistance in CRPC models.

Conclusions:

• The findings highlight Z15 as a promising therapeutic candidate for CRPC, particularly in cases resistant to existing treatments.
• The dual mechanism of AR antagonism and degradation represents a synergistic strategy for effectively treating advanced prostate cancer.