RESUMEN
Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.
Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Receptores Androgénicos/genética , Transcripción Genética/efectos de los fármacos , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Línea Celular Tumoral , Quinasa 9 Dependiente de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Neoplasias de la Próstata Resistentes a la Castración/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, µ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
Asunto(s)
Receptores Opioides/agonistas , Bibliotecas de Moléculas Pequeñas/química , Compuestos de Espiro/química , Animales , Ansiedad/tratamiento farmacológico , Modelos Animales de Enfermedad , Actividad Motora/efectos de los fármacos , Péptidos Opioides/química , Péptidos Opioides/metabolismo , Unión Proteica , Ratas , Receptores Opioides/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Relación Estructura-Actividad , Receptor de Nociceptina , NociceptinaRESUMEN
A novel series of indoles and 1H-pyrrolo[2,3-b]pyridines having a piperidine ring at the 3-position were synthesized and found to bind with high affinity to the ORL-1 receptor. Structure-activity relationships at the piperidine nitrogen were investigated in each series. Substitution on the phenyl ring and nitrogen atom of the indole and 1H-pyrrolo[2,3-b]pyridine cores generated several selective high-affinity ligands that were agonists of the ORL-1 receptor.
Asunto(s)
Indoles/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Pirroles/farmacología , Receptores Opioides/agonistas , Sitios de Unión , Indoles/síntesis química , Indoles/química , Ligandos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piridinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
A novel series of indolin-2-ones having a spirocyclic piperidine ring at the 3-position was synthesized and found to bind with high affinity to the ORL-1 receptor. Structure-activity relationships at the piperidine nitrogen were investigated. Substitution on the phenyl ring and nitrogen atom of the indolin-2-one core generated several selective high-affinity ligands that were antagonists of the ORL-1 receptor.
