M3258 is a selective inhibitor of the immunoproteasome subunit LMP7 (β5i) delivering efficacy in multiple myeloma models

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

Authors: Michael P. Sanderson (Merck KGaA) , Manja Friese-Hamim (Merck KGaA) , Gina Walter-Bausch (Merck KGaA) , Michael Busch (Blood Systems Research Institute) , Stefanie Gaus (Merck KGaA) , Djordje Musil (Merck Serono) , Felix Rohdich (Merck KGaA) , Ugo Zanelli (Galderma SA) , Sondra L. Downey-Kopyscinski (Dana-Farber Cancer Institute) , Constantine S. Mitsiades (Harvard Medical School) , Oliver Schadt (Merck KGaA) , Markus Klein (Merck KGaA) , Christina Esdar (Merck KGaA)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Molecular Cancer Therapeutics

State: Published (Approved)
Published: May 2021

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 (MM), 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 MM xenograft models, including a novel model of the human bone niche of MM. M3258 treatment led to a significant and prolonged suppression of tumor LMP7 activity and ubiquitinated protein turnover and the induction of apoptosis in MM cells both in vitro and in vivo. Furthermore, M3258 showed superior antitumor efficacy in selected MM and mantle cell lymphoma xenograft models compared to the approved non-selective proteasome inhibitors bortezomib and ixazomib. The differentiated preclinical profile of M3258 supported the initiation of a phase I study in MM patients (NCT04075721).

Diamond Keywords: Blood Cancer

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography

Added On: 09/06/2021 13:55

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)