4HY0

Crystal structure of XIAP BIR3 with T3256336

Summary for 4HY0

• Entry DOI: 10.2210/pdb4hy0/pdb
• Related PRD ID: PRD_001138
• Descriptor: E3 ubiquitin-protein ligase XIAP, ZINC ION, (3S,7R,8aR)-2-{(2S)-2-(4,4-difluorocyclohexyl)-2-[(N-methyl-L-alanyl)amino]acetyl}-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-7-ethoxyoctahydropyrrolo[1,2-a]pyrazine-3-carboxamide, ... (4 entities in total)
• Functional Keywords: bir3, baculoviral iap repeat-containing protein 4, apoptotic suppressor. inhibitor of caspase-3, -7 and -9., interacts with smac and with prss25, xiap, birc4, x-linked inhibitor of apoptosis, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P98170
• Total number of polymer chains: 8
• Total formula weight: 119423.14

Authors

Snell, G.S.,Dougan, D.R. (deposition date: 2012-11-12, release date: 2013-01-30, Last modification date: 2024-02-28)

Primary citation

Hashimoto, K.,Saito, B.,Miyamoto, N.,Oguro, Y.,Tomita, D.,Shiokawa, Z.,Asano, M.,Kakei, H.,Taya, N.,Kawasaki, M.,Sumi, H.,Yabuki, M.,Iwai, K.,Yoshida, S.,Yoshimatsu, M.,Aoyama, K.,Kosugi, Y.,Kojima, T.,Morishita, N.,Dougan, D.R.,Snell, G.P.,Imamura, S.,Ishikawa, T.
Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic.
J.Med.Chem., 56:1228-1246, 2013

PubMed Abstract: To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC(50): 1.3 nM) and XIAP (IC(50): 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).

PubMed: 23298277
DOI: 10.1021/jm301674z

Experimental method

X-RAY DIFFRACTION (2.84 Å)