PXD036170-2

PXD036170 is an original dataset announced via ProteomeXchange.

Title	Redirecting the neo-substrate specificity of Cereblon-targeting PROTACs to Helios
Description	Immunomodulatory imide drugs (IMiDs), such as thalidomide and its analogues, are some of the most commonly utilized E3 ligase ligands for the development of proteolysis targeting chimeras (PROTACs). While the canonical neo-substrates of IMiDs (i.e., Ikaros and Aiolos) are often considered to be unwanted off-targets of PROTACs, maintaining the degradation of these neo-substrates also provides the opportunity to synergistically degrade multiple proteins with a single compound. Here, we report the development of ALV-07-082-03, a CDK4/CDK6/Helios triple degrader that consists of palbociclib, an FDA-approved CDK4/6 inhibitor, conjugated to DKY709, a novel IMiD-based Helios degrader. Pharmacological co-degradation of CDK4/6 and Helios resulted in potent suppression of downstream signaling and proliferation in cancer cells, as well as enhanced de-repression of IL-2 secretion. Thus, not only do we demonstrate the possibility of rationally re-directing the neo-substrate specificity of PROTACs by incorporating alternative molecular glue molecules as E3 ligase ligands, but our findings also suggest that co-targeting CDK4/6 and Helios may have synergistic effects.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:58:03.990.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-19 01:30:48	ID requested
1	2022-09-07 12:05:17	announced
⏵ 2	2023-11-14 08:58:04	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: Targeted Protein Degradation, Degrader, Helios, CDK4, PROTAC, CDK6

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036170
     1. Label: PRIDE project
     2. Name: Redirecting the neo-substrate specificity of Cereblon-targeting PROTACs to Helios