Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres

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 Ki’s of 20–30 nM against ML-IAP and 50–60 nM against XIAP-BIR3.

The co-crystal structure of peptide 1 with an ML-IAP BIR construct was used to guide amide bond replacement with either a thiazole or benzothiazole, leading to potent IAP antagonists such as 11e and 26d.Figure optionsDownload as PowerPoint slide