4HY0

Crystal structure of XIAP BIR3 with T3256336

4HY0 の概要

• エントリーDOI: 10.2210/pdb4hy0/pdb
• 関連するBIRD辞書のPRD_ID: PRD_001138
• 分子名称: 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)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P98170
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 119423.14

構造登録者

Snell, G.S.,Dougan, D.R. (登録日: 2012-11-12, 公開日: 2013-01-30, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.84 Å)