Discovery of JNJ-63576253, a Next-Generation Androgen Receptor Antagonist Active Against Wild-Type and Clinically...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) often develops resistance to second-generation androgen receptor (AR) pathway inhibitors.
• AR ligand-binding domain mutations can convert AR antagonists into agonists, promoting disease progression.
• There is an unmet clinical need for novel therapeutics targeting resistant AR signaling in mCRPC.

Purpose of the Study:

• To report the discovery and preclinical characterization of JNJ-63576253, a novel AR pathway inhibitor.
• To evaluate the efficacy of JNJ-63576253 in preclinical models of prostate cancer with AR pathway alterations.
• To identify JNJ-63576253 as a potential clinical candidate for mCRPC patients resistant to existing treatments.

Main Methods:

• Discovery and synthesis of JNJ-63576253.
• Preclinical testing in cellular and animal models of human prostate adenocarcinoma.
• Assessment of AR signaling inhibition and anti-tumor activity.

Main Results:

• JNJ-63576253 potently inhibits AR signaling in models of prostate adenocarcinoma.
• The compound demonstrates effectiveness in preclinical models relevant to AR resistance mechanisms.
• JNJ-63576253 is advancing as a clinical candidate.

Conclusions:

• JNJ-63576253 represents a promising next-generation AR pathway inhibitor.
• This agent has the potential to treat patients with mCRPC who have progressed on or are unresponsive to current AR-targeted therapies.
• Further clinical investigation of JNJ-63576253 is warranted for AR-driven prostate cancer.