RESUMEN

Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for activating many signaling proteins and is a promising target in tumor biology. We have identified small-molecule benzisoxazole derivatives as Hsp90 inhibitors. Crystallographic studies show that these compounds bind in the ATP binding pocket interacting with the Asp93. Structure based optimization led to the identification of potent analogues, such as 13, with good biochemical profiles.

Asunto(s)

Antineoplásicos/síntesis química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoxazoles/síntesis química , Adenosina Trifosfato/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Células K562 , Modelos Moleculares , Conformación Proteica , Relación Estructura-Actividad