Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres

Frederick Cohen; Michael F T Koehler; Philippe Bergeron; Linda O Elliott; John A Flygare; Matthew C Franklin; Lewis Gazzard; Stephen F Keteltas; Kevin Lau; Cuong Q Ly; Vickie Tsui; Wayne J Fairbrother

doi:10.1016/j.bmcl.2010.02.021

Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2229-33. doi: 10.1016/j.bmcl.2010.02.021. Epub 2010 Feb 8.

Authors

Frederick Cohen¹, Michael F T Koehler, Philippe Bergeron, Linda O Elliott, John A Flygare, Matthew C Franklin, Lewis Gazzard, Stephen F Keteltas, Kevin Lau, Cuong Q Ly, Vickie Tsui, Wayne J Fairbrother

Affiliation

¹ Department of Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA. fcohen@gene.com

PMID: 20189383
DOI: 10.1016/j.bmcl.2010.02.021

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amides / chemistry*
Amides / pharmacology*
Binding Sites
Biomimetics
Crystallography, X-Ray
Humans
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
Inhibitor of Apoptosis Proteins / metabolism
Models, Molecular
Peptides / chemistry*
Peptides / metabolism
Thiazoles / chemistry*
Thiazoles / pharmacology*

Substances

Amides
Inhibitor of Apoptosis Proteins
Peptides
Thiazoles