RESUMEN
The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lisofosfolipasa/antagonistas & inhibidores , Lisofosfolípidos/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacocinética , Humanos , Lisofosfolipasa/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologíaRESUMEN
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
Asunto(s)
Antineoplásicos/química , Diaminas/química , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirimidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular , Diaminas/síntesis química , Diaminas/farmacología , Descubrimiento de Drogas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Morfolinas/síntesis química , Morfolinas/farmacología , Complejos Multiproteicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Proteínas , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.