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7awe

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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

Structural highlights

7awe is a 20 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.288Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PSA6_HUMAN The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity.

Publication Abstract from PubMed

Large multifunctional peptidase 7 (LMP7/beta5i/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 in vitro and in vivo 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).

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (beta5i) Delivering Efficacy in Multiple Myeloma Models.,Sanderson MP, Friese-Hamim M, Walter-Bausch G, Busch M, Gaus S, Musil D, Rohdich F, Zanelli U, Downey-Kopyscinski SL, Mitsiades CS, Schadt O, Klein M, Esdar C Mol Cancer Ther. 2021 Aug;20(8):1378-1387. doi: 10.1158/1535-7163.MCT-21-0005. , Epub 2021 May 27. PMID:34045234^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sanderson MP, Friese-Hamim M, Walter-Bausch G, Busch M, Gaus S, Musil D, Rohdich F, Zanelli U, Downey-Kopyscinski SL, Mitsiades CS, Schadt O, Klein M, Esdar C. M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) Delivering Efficacy in Multiple Myeloma Models. Mol Cancer Ther. 2021 Aug;20(8):1378-1387. PMID:34045234 doi:10.1158/1535-7163.MCT-21-0005