PXD046286

PXD046286 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 downregulated 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 confirm that this binder can be functionalized into an efficient DCAF1-BRD9-PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4(DCAF1) 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	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:17:56.545.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD046286
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Andreas Hofmann
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-22 06:21:35	ID requested
1	2023-12-18 03:21:01	announced
⏵ 2	2024-10-22 06:17:56	announced	2024-10-22: Updated project metadata.

10.1038/S41467-023-44237-4;

10.6019/PXD046286;

submitter keyword: TMT, DCAF1,TPD, PROTAC

Andreas Josef
contact affiliation	Biomedical Research Novartis Pharma AG
contact email	andreas.hofmann@novartis.com
lab head
Andreas Hofmann
contact affiliation	NIBR
contact email	andreas.hofmann@novartis.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046286
     1. Label: PRIDE project
     2. Name: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance