PXD047347

PXD047347 is an original dataset announced via ProteomeXchange.

Title	DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
Description	Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be down-regulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We con firm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.
HostingRepository	PRIDE
AnnounceDate	2023-12-18
AnnouncementXML	Submission_2023-12-18_08:21:06.621.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jason Thomas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-28 11:23:03	ID requested
⏵ 1	2023-12-18 08:21:07	announced

10.1038/S41467-023-44237-4;

submitter keyword: chemical proteomics

Markus Schirle
contact affiliation	Novartis Institutes for Biomedical Research
contact email	markus.schirle@novartis.com
lab head
Jason Thomas
contact affiliation	Novartis Biomedical Research
contact email	jason.thomas@novartis.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047347
     1. Label: PRIDE project
     2. Name: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance