RESUMEN
Corramycin 1 is a novel zwitterionic antibacterial peptide isolated from a culture of the myxobacterium Corallococcus coralloides. Though Corramycin displayed a narrow spectrum and modest MICs against sensitive bacteria, its ADMET and physchem profile as well as its high tolerability in mice along with an outstanding in vivo efficacy in an Escherichia coli septicemia mouse model were promising and prompted us to embark on an optimization program aiming at enlarging the spectrum and at increasing the antibacterial activities by modulating membrane permeability. Scanning the peptidic moiety by the Ala-scan strategy followed by key stabilization and introduction of groups such as a primary amine or siderophore allowed us to enlarge the spectrum and increase the overall developability profile. The optimized Corramycin 28 showed an improved mouse IV PK and a broader spectrum with high potency against key Gram-negative bacteria that translated into excellent efficacy in several in vivo mouse infection models.
Asunto(s)
Antibacterianos , Infecciones por Escherichia coli , Ratones , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/química , Bacterias Gramnegativas , Bacterias , Pruebas de Sensibilidad MicrobianaRESUMEN
The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression in a broad range of malignancies have been demonstrated and have prompted intensive search for small molecule Aurora inhibitors. Indeed, over 10 of them have reached the clinic as potential anticancer therapies. We report herein the discovery and optimization of a novel series of tricyclic molecules that has led to SAR156497, an exquisitely selective Aurora A, B, and C inhibitor with in vitro and in vivo efficacy. We also provide insights into its mode of binding to its target proteins, which could explain its selectivity.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasas/antagonistas & inhibidores , Bencimidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinolonas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/química , Aurora Quinasa A/metabolismo , Aurora Quinasa B/antagonistas & inhibidores , Aurora Quinasa B/química , Aurora Quinasa B/metabolismo , Aurora Quinasa C/antagonistas & inhibidores , Aurora Quinasa C/química , Aurora Quinasa C/metabolismo , Aurora Quinasas/química , Aurora Quinasas/metabolismo , Bencimidazoles/química , Bencimidazoles/metabolismo , Femenino , Células HCT116 , Humanos , Ratones SCID , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Quinolonas/química , Quinolonas/metabolismo , Células Sf9 , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kß in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kß-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kß inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110ß with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.
Asunto(s)
Antineoplásicos/química , Indoles/química , Neoplasias/tratamiento farmacológico , Fosfohidrolasa PTEN/deficiencia , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirimidinonas/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Xenoinjertos , Humanos , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Microsomas Hepáticos/metabolismo , Conformación Molecular , Simulación del Acoplamiento Molecular , Trasplante de Neoplasias , Neoplasias/enzimología , Fosfohidrolasa PTEN/genética , Unión Proteica , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Ratas , Ratas Desnudas , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.