RESUMEN
Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Fosfatidilinositol 3-Quinasas Clase III/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Neoplasias/tratamiento farmacológico , Pirimidinonas/farmacología , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Área Bajo la Curva , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Células CACO-2 , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas Clase III/química , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Cristalografía por Rayos X , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Masculino , Ratones SCID , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Neoplasias/patología , Unión Proteica , Estructura Terciaria de Proteína , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratas Sprague-Dawley , Homología de Secuencia de Aminoácido , Termodinámica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Defects in insulin production and signaling are suspected to share a key role in diabetes and Alzheimer disease (AD), two age-related pathologies. In this study, we investigated the interrelation between AD and diabetes using a high-fat diet (HFD) in a mouse model of genetically induced AD-like neuropathology (3xTg-AD). We first observed that cerebral expression of human AD transgenes led to peripheral glucose intolerance, associated with pancreatic human Aß accumulation. High-fat diet enhanced glucose intolerance, brain soluble Aß, and memory impairment in 3xTg-AD mice. Strikingly, a single insulin injection reversed the deleterious effects of HFD on memory and soluble Aß levels, partly through changes in Aß production and/or clearance. Our results are consistent with the development of a vicious cycle between AD and diabetes, potentiating both peripheral metabolic disorders and AD neuropathology. The capacity of insulin to rapidly break the deleterious effects of this cycle on soluble Aß concentrations and memory has important therapeutic implications.