RESUMEN
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
One of the key elements in the drug discovery process is the use of automation to synthesize libraries of compounds for biological screening. The "split-and-mix" approaches in combinatorial chemistry have been recognized as extremely powerful techniques to access large numbers of compounds, while requiring only few reaction steps. However, the need for effective encoding/deconvolution strategies and demands for larger amounts of compounds have somewhat limited the use of these techniques in the pharmaceutical industry. In this paper, we describe a concept of directed sort and combine synthesis with spatially arranged arrays of macroscopic supports. Such a concept attempts to balance the number of reaction steps, the confidence in compound identity, and the quantity of synthesized compounds. Using three-dimensional arrays of frames each containing a two-dimensional array of macroscopic solid supports, we have conceptualized and developed a modular semiautomated system with a capacity of up to 100 000 compounds per batch. Modularity of this system enables flexibility either to produce large diverse combinatorial libraries or to synthesize more focused smaller libraries, both as single compounds in 12-15 micromol quantities. This method using sortable and spatially addressed arrays is exemplified by the synthesis of a 15 360 compound library.