PXD050568-2

PXD050568 is an original dataset announced via ProteomeXchange.

Title	Targeted MS assay to evaluate Cereblon neosubstrate changes in rabbit embryos following maternal administration of IMiDs
Description	Targeted 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.
HostingRepository	PanoramaPublic
AnnounceDate	2024-07-02
AnnouncementXML	Submission_2024-07-02_08:39:55.223.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Joel Federspiel
SpeciesList	scientific name: Oryctolagus cuniculus; NCBI TaxID: 9986;
ModificationList	Carbamidomethyl; Label:13C(6)15N(2); Label:13C(6)15N(4)
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-12 20:53:54	ID requested
1	2024-06-06 12:20:36	announced
⏵ 2	2024-07-02 08:39:56	announced	: Added PubMed Id

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]

submitter keyword: CRBN, IMiD, PRM, IA, Neosubstrate

Mireia Fernandez Ocana
contact affiliation	Pfizer Inc, DSRD
contact email	mireia.fernandezocana@pfizer.com
lab head
Joel Federspiel
contact affiliation	Pfizer Inc, DSRD
contact email	joel.federspiel@pfizer.com
dataset submitter

Panorama Public dataset URI