Discovery of the First-in-Class RORγ Covalent Inhibitors for Treatment of Castration-Resistant Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Receptor-related orphan receptor γ (RORγ) is a key driver in castration-resistant prostate cancers (CRPC).
• RORγ promotes androgen receptor (AR) overexpression, making it a therapeutic target for advanced prostate cancers.

Purpose of the Study:

• To identify and characterize the first-in-class RORγ covalent inhibitor.
• To evaluate the efficacy of the novel inhibitor in preclinical models of CRPC.

Main Methods:

• Structure-based drug design and structure-activity relationship (SAR) exploration.
• Mass spectrometry to validate covalent inhibition mechanism.
• In vitro assays assessing transcriptional activity, cell proliferation, colony formation, and apoptosis.
• In vivo studies using a 22Rv1 mouse tumor xenograft model.

Main Results:

• Compound 29 was identified as a potent and selective RORγ covalent inhibitor.
• Compound 29 significantly inhibited RORγ transcriptional activity and suppressed AR and AR-targeted gene expression.
• Compound 29 demonstrated superior efficacy in inhibiting CRPC cell proliferation and inducing apoptosis compared to controls.
• Compound 29 markedly suppressed tumor growth in vivo with good safety.

Conclusions:

• Compound 29 represents a promising first-in-class RORγ covalent inhibitor for advanced prostate cancer treatment.
• The findings support RORγ as a viable therapeutic target in CRPC, with compound 29 as a lead candidate.