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

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Departments of Discovery Chemistry, Discovery Technologies, §Non-clinical Safety, Early ADME, and Discovery Oncology, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, United States
*E-mail: [email protected]. Phone: 973-498-8986.
Cite this: J. Med. Chem. 2013, 56, 20, 7788–7803
Publication Date (Web):October 7, 2013
https://doi.org/10.1021/jm400732v
Copyright © 2013 American Chemical Society

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    Abstract

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    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.

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    Full procedures for compounds 7 through 26af, crystallographic method, data collection, and refinement statistics. This material is available free of charge via the Internet at http://pubs.acs.org.

    Accession Codes

    The PDB ID code for 21j bound to XIAP BIR2 shown in Figure 3 is 4KJU.

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