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

Summary for 7AWE

• Entry DOI: 10.2210/pdb7awe/pdb
• Descriptor: Proteasome subunit alpha type-6, Proteasome subunit beta type-3, Proteasome subunit beta type-2, ... (18 entities in total)
• Functional Keywords: multicatalytic proteinase, 20s proteasome, protease, hydrolase, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 28
• Total formula weight: 695590.05

Authors

Musil, D.,Klein, M. (deposition date: 2020-11-06, release date: 2021-06-09, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.288 Å)