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PXD050568-2

PXD050568 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTargeted MS assay to evaluate Cereblon neosubstrate changes in rabbit embryos following maternal administration of IMiDs
DescriptionTargeted protein degradation is the selective removal of a protein of interest through hijacking intracellular protein cleanup machinery. This rapidly growing field currently relies heavily on the use of the E3 ligase Cereblon (CRBN) to target proteins for degradation, including the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide which work through a molecular glue mechanism of action with CRBN. While CRBN recruitment can result in degradation of a specific protein of interest (e.g. efficacy), degradation of other proteins (called CRBN neosubstrates) also occurs. Degradation of one or more of these CRBN neosubstrates is believed to play an important role in thalidomide-related developmental toxicity observed in rabbits and primates. We identified a set of 25 proteins of interest associated with CRBN-related protein homeostasis and/or embryo/fetal development. We developed a targeted assay for these proteins combining peptide immunoaffinity enrichment and high-resolution mass spectrometry and successfully applied this assay to rabbit embryo samples from pregnant rabbits dosed with three IMiDs. We confirmed previously reported in vivo decreases in neosubstrates like SALL4, as well as provided evidence of neosubstrate changes for proteins only examined in vitro previously. While there were many proteins that were similarly decreased by all three IMiDs, no compound had the exact same neosubstrate degradation profile as another. We compared our data to previous literature reports of IMiD induced degradation and known developmental biology associations. Based on our observations, we recommend monitoring at least a major subset of these neosubstrates in a developmental test system to improve CRBN-binding compound-specific risk assessment. A strength of our assay is that it is configurable, and the target list can be readily adapted to focus on only a subset of proteins of interest or expanded to incorporate new findings as additional information about CRBN biology is discovered.
HostingRepositoryPanoramaPublic
AnnounceDate2024-07-02
AnnouncementXMLSubmission_2024-07-02_08:39:55.223.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterJoel Federspiel
SpeciesList scientific name: Oryctolagus cuniculus; NCBI TaxID: 9986;
ModificationListCarbamidomethyl; Label:13C(6)15N(2); Label:13C(6)15N(4)
InstrumentOrbitrap Eclipse
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-03-12 20:53:54ID requested
12024-06-06 12:20:36announced
22024-07-02 08:39:56announced: Added PubMed Id
Publication List
Federspiel JD, Catlin NR, Nowland WS, Stethem CM, Mathialagan N, Fernandez Oca, ñ, a M, Bowman CJ, Differential Analysis of Cereblon Neosubstrates in Rabbit Embryos Using Targeted Proteomics. Mol Cell Proteomics, 23(7):100797(2024) [pubmed]
Keyword List
submitter keyword: CRBN, IMiD, PRM, IA, Neosubstrate
Contact List
Mireia Fernandez Ocana
contact affiliationPfizer Inc, DSRD
contact emailmireia.fernandezocana@pfizer.com
lab head
Joel Federspiel
contact affiliationPfizer Inc, DSRD
contact emailjoel.federspiel@pfizer.com
dataset submitter
Full Dataset Link List
Panorama Public dataset URI