RESUMEN
More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Animales , Neoplasias de la Mama/metabolismo , Cristalografía por Rayos X , Perros , Resistencia a Antineoplásicos , Femenino , Semivida , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Ratones , Modelos Moleculares , Ratas , Receptores de Estrógenos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kß isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kß. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Pirimidinonas/química , Pirimidinonas/farmacología , Anilidas/química , Anilidas/farmacocinética , Anilidas/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Cristalografía por Rayos X , Femenino , Eliminación de Gen , Humanos , Masculino , Ratones , Ratones SCID , Modelos Moleculares , Fosfohidrolasa PTEN/genética , Próstata/citología , Próstata/efectos de los fármacos , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Pirimidinonas/farmacocinética , Relación Estructura-ActividadRESUMEN
Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kß has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kß-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kß and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kß isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.