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J Med Chem ; 52(2): 379-88, 2009 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-19143567


Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

Bencimidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Bencimidazoles/química , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/farmacología
J Biol Chem ; 277(46): 44164-70, 2002 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-12218057


Receptor tyrosine kinases of the Axl family are activated by Gas6, the product of growth arrest-specific gene 6. Gas6-Axl signaling is implicated in cell survival, adhesion, and migration. The receptor-binding site of Gas6 is located within a C-terminal pair of laminin G-like (LG) domains that do not resemble any other receptor tyrosine kinase ligand. We report the crystal structure at 2.2-A resolution of a Gas6 fragment spanning both LG domains (Gas6-LG). The structure reveals a V-shaped arrangement of LG domains strengthened by an interdomain calcium-binding site. LG2 of Gas6-LG contains two unusual features: an alpha-helix cradled by one edge of the LG beta-sandwich and a conspicuous patch of surface-exposed hydrophobic residues. Mutagenesis of some residues in this patch reduces Gas6-LG binding to the extracellular domain of Axl as well as Axl activation in glioblastoma cells, identifying a component of the receptor-binding site of Gas6.

Péptidos y Proteínas de Señalización Intercelular , Laminina/química , Proteínas/química , Secuencia de Aminoácidos , Sitios de Unión , Calcio/metabolismo , Cristalografía por Rayos X , Medio de Cultivo Libre de Suero/farmacología , ADN Complementario/metabolismo , Electroforesis en Gel de Poliacrilamida , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Unión Proteica , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Células Tumorales Cultivadas