4KJU

Crystal structure of XIAP-Bir2 with a bound benzodiazepinone inhibitor.

Summary for 4KJU

• Entry DOI: 10.2210/pdb4kju/pdb
• Related: 4J3Y 4J44 4J45 4J46 4J47 4J48
• Descriptor: E3 ubiquitin-protein ligase XIAP, ZINC ION, N-{(3S)-5-(4-aminobenzoyl)-1-[(2-methoxynaphthalen-1-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}-N~2~-methyl-L-alaninamide, ... (4 entities in total)
• Functional Keywords: xiap inhibitors, bir2, benzodiazepinone, oncology, caspase, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P98170
• Total number of polymer chains: 2
• Total formula weight: 20554.72

Authors

Lukacs, C.M.,Janson, C.A. (deposition date: 2013-05-03, release date: 2013-11-27, Last modification date: 2023-09-20)

Primary citation

Kester, R.F.,Donnell, A.F.,Lou, Y.,Remiszewski, S.W.,Lombardo, L.J.,Chen, S.,Le, N.T.,Lo, J.,Moliterni, J.A.,Han, X.,Hogg, J.H.,Liang, W.,Michoud, C.,Rupert, K.C.,Mischke, S.,Le, K.,Weisel, M.,Janson, C.A.,Lukacs, C.M.,Fretland, A.J.,Hong, K.,Polonskaia, A.,Gao, L.,Li, S.,Solis, D.S.,Aguilar, D.,Tardell, C.,Dvorozniak, M.,Tannu, S.,Lee, E.C.,Schutt, A.D.,Goggin, B.
Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain.
J.Med.Chem., 56:7788-7803, 2013

PubMed Abstract: 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.

PubMed: 24093940
DOI: 10.1021/jm400732v

Experimental method

X-RAY DIFFRACTION (1.6 Å)