7AWE

HUMAN IMMUNOPROTEASOME 20S PARTICLE IN COMPLEX WITH [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid

7AWE の概要

• エントリーDOI: 10.2210/pdb7awe/pdb
• 分子名称: Proteasome subunit alpha type-6, Proteasome subunit beta type-3, Proteasome subunit beta type-2, ... (18 entities in total)
• 機能のキーワード: multicatalytic proteinase, 20s proteasome, protease, hydrolase, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 695590.05

構造登録者

Musil, D.,Klein, M. (登録日: 2020-11-06, 公開日: 2021-06-09, 最終更新日: 2024-11-20)

主引用文献

Sanderson, M.P.,Friese-Hamim, M.,Walter-Bausch, G.,Busch, M.,Gaus, S.,Musil, D.,Rohdich, F.,Zanelli, U.,Downey-Kopyscinski, S.L.,Mitsiades, C.S.,Schadt, O.,Klein, M.,Esdar, C.
M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 ( beta 5i) Delivering Efficacy in Multiple Myeloma Models.
Mol.Cancer Ther., 20:1378-1387, 2021

PubMed Abstract: Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally bioavailable, potent, reversible and highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in multiple myeloma xenograft models, including a novel model of the human bone niche of multiple myeloma. M3258 treatment led to a significant and prolonged suppression of tumor LMP7 activity and ubiquitinated protein turnover and the induction of apoptosis in multiple myeloma cells both and Furthermore, M3258 showed superior antitumor efficacy in selected multiple myeloma and mantle cell lymphoma xenograft models compared with the approved nonselective proteasome inhibitors bortezomib and ixazomib. The differentiated preclinical profile of M3258 supported the initiation of a phase I study in patients with multiple myeloma (NCT04075721).

PubMed: 34045234
DOI: 10.1158/1535-7163.MCT-21-0005

実験手法

X-RAY DIFFRACTION (2.288 Å)