PXD061058

PXD061058 is an original dataset announced via ProteomeXchange.

Title	Identification of Omaveloxolone as An Endoplasmic Reticulum Associated Degradation Inhibitor That Induces ER Stress and Early Apoptotic Signaling in Multiple Myeloma
Description	Multiple myeloma (MM) is an incurable plasma cell neoplasm that is highly reliant on endoplasmic reticulum associated degradation (ERAD) to maintain protein homeostasis. Disrupting ERAD activity has been proposed to be preferentially cytotoxic to malignant plasma cells and may overcome proteasome inhibitor resistance, however, the identification of novel inhibitors has been limited. We developed a screening approach to identify ERAD modulators and applied it in the FDA repurposing library. Here we report a novel compound, omaveloxolone (RTA408), inhibits ERAD activity, rapidly induces the unfolded protein response, and leads to rapid induction of caspase 8 mediated apoptotic signaling in MM. Furthermore, we find that unlike proteasome inhibitors (PIs), RTA408 leads to sustained inhibition of ERAD protein degradation without affecting cytosolic protein degradation, which may address key mechanisms of PI resistance. Importantly we find that ERAD inhibition by RTA408 is cytotoxic in malignant plasma cells with PI resistance and has in vivo anti-myeloma activity. Altogether these studies provide pre-clinical evidence for application of a novel ERAD inhibitor in MM and highlight how it can be leveraged to study ER protein regulation in MM.
HostingRepository	PRIDE
AnnounceDate	2026-03-09
AnnouncementXML	Submission_2026-03-09_09:42:54.240.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Erin Kropp
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-21 08:38:20	ID requested
⏵ 1	2026-03-09 09:42:54	announced

10.1038/S41419-026-08526-2;

submitter keyword: Caspase 8,Multiple Myeloma Endoplasmic Reticulum Associated Degradation Omaveloxolone, NRF2 Endoplasmic Reticulum, HERP1, Unfolded Protein Response, PERK HERPUD1, RTA408, RIPK1

Qing Li1
contact affiliation	Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan
contact email	lqing@med.umich.edu
lab head
Erin Kropp
contact affiliation	University of Michigan
contact email	kroppe@umich.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061058
     1. Label: PRIDE project
     2. Name: Identification of Omaveloxolone as An Endoplasmic Reticulum Associated Degradation Inhibitor That Induces ER Stress and Early Apoptotic Signaling in Multiple Myeloma