Portal de Periódicos da CAPES

Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain

2013; American Chemical Society; Volume: 56; Issue: 20 Linguagem: Inglês

10.1021/jm400732v

1520-4804

Robert F. Kester, Andrew F. Donnell, Yan Lou, Stacy Remiszewski, Louis J. Lombardo, Shaoqing Chen, Nam T. Le, Jennifer Lo, John Moliterni, Xiaochun Han, J. Heather Hogg, Weiling Liang, Christophe Michoud, Kenneth C. Rupert, Steven Mischke, Le Kang, Martin Weisel, Cheryl A. Janson, Christine Lukacs, Adrian J. Fretland, Kyoungja Hong, Ann Polonskaia, Lin Gao, Shirley Xin Li, Dave S. Solis, Doug Aguilar, Christine Tardell, Mark Dvorozniak, Shahid Tannu, Edmund C. Lee, Andy D. Schutt, Barry S. Goggin,

Bacillus and Francisella bacterial research

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.