Abstract
Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).
MeSH terms
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Androgen Receptor Antagonists / pharmacokinetics
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Androgen Receptor Antagonists / pharmacology*
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Androgen Receptor Antagonists / therapeutic use
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Animals
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Biotransformation
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Cell Line, Tumor
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Dogs
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Drug Discovery
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Drug Resistance, Neoplasm / genetics
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Hepatocytes / metabolism
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Humans
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Male
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Models, Molecular
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Mutation
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Nitriles / pharmacokinetics
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Nitriles / pharmacology*
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Nitriles / therapeutic use
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Picolines / pharmacokinetics
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Picolines / pharmacology*
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Picolines / therapeutic use
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Piperidines / pharmacokinetics
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Piperidines / pharmacology*
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Piperidines / therapeutic use
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms, Castration-Resistant / drug therapy*
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Prostatic Neoplasms, Castration-Resistant / genetics
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Pyridines / therapeutic use
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Rats
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology*
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Spiro Compounds / therapeutic use
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Structure-Activity Relationship
Substances
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Androgen Receptor Antagonists
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JNJ-63576253
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Nitriles
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Picolines
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Piperidines
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Pyridines
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Spiro Compounds