RESUMEN
A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compounds, 19a and 33b, were found to have K(i)'s of 20-30 nM against ML-IAP and 50-60 nM against XIAP-BIR3.
Asunto(s)
Amidas/química , Amidas/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Péptidos/química , Tiazoles/química , Tiazoles/farmacología , Sitios de Unión , Biomimética , Cristalografía por Rayos X , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Modelos Moleculares , Péptidos/metabolismoRESUMEN
A series of IAP antagonists based on an azabicyclooctane scaffold was designed and synthesized. The most potent of these compounds, 14b, binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domain of c-IAP1 with K(i) values of 140, 38, and 33 nM, respectively. These compounds promote degradation of c-IAP1, activate caspases, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Finally, compound 14b inhibits tumor growth when dosed orally in a breast cancer xenograft model.