4MTI

Crystal structure of cIAP1 BIR3 bound to T3258042

4MTI の概要

• エントリーDOI: 10.2210/pdb4mti/pdb
• 関連するPDBエントリー: 4MU7
• 分子名称: Baculoviral IAP repeat-containing protein 2, ZINC ION, (3S,8aR)-2-[(2S)-2-cyclohexyl-2-{[(2S)-2-(methylamino)butanoyl]amino}acetyl]-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]octahydropyrrolo[1,2-a]pyrazine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: ring-type zinc finger, ligase, apoptosis inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q13490
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27799.89

構造登録者

Snell, G.P.,Dougan, D.R. (登録日: 2013-09-19, 公開日: 2013-12-11, 最終更新日: 2024-02-28)

主引用文献

Shiokawa, Z.,Hashimoto, K.,Saito, B.,Oguro, Y.,Sumi, H.,Yabuki, M.,Yoshimatsu, M.,Kosugi, Y.,Debori, Y.,Morishita, N.,Dougan, D.R.,Snell, G.P.,Yoshida, S.,Ishikawa, T.
Design, synthesis, and biological activities of novel hexahydropyrazino[1,2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells.
Bioorg.Med.Chem., 21:7938-7954, 2013

PubMed Abstract: We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23 nM and cellular IAP [cIAP]: IC50 1.1 nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8 nM) with high permeability and low potential of MDR1 substrate.

PubMed: 24169315
DOI: 10.1016/j.bmc.2013.09.067

実験手法

X-RAY DIFFRACTION (2.15 Å)