RESUMO
Androgen receptor (AR) transcriptional reactivation plays a key role in the development and progression of lethal castration-resistant prostate cancer (CRPC). Recurrent alterations in the AR enable persistent AR pathway signaling and drive resistance to the treatment of second-generation antiandrogens. AR F877L, a point mutation in the ligand binding domain of the AR, was identified in patients who acquired resistance to enzalutamide or apalutamide. In parallel to our previous structure-activity relationship (SAR) studies of compound 4 (JNJ-pan-AR) and clinical stage compound 5 (JNJ-63576253), we discovered additional AR antagonists that provide opportunities for future development. Here we report a highly potent series of spirocyclic thiohydantoins as AR antagonists for the treatment of the F877L mutant and wild-type CRPC.
RESUMO
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).
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Nitrilas/farmacologia , Picolinas/farmacologia , Piperidinas/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Piridinas/farmacologia , Compostos de Espiro/farmacologia , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Biotransformação , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/genética , Hepatócitos/metabolismo , Humanos , Masculino , Modelos Moleculares , Mutação , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Picolinas/farmacocinética , Picolinas/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Compostos de Espiro/farmacocinética , Compostos de Espiro/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.