Proteomics

Dataset Information

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DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance


ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Cell Culture, Early Embryonic Cell, Kidney

DISEASE(S): Lymphoma

SUBMITTER: Andreas Hofmann  

LAB HEAD: Andreas Josef

PROVIDER: PXD046286 | Pride | 2023-12-18

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
PXP0425_KEAP1_Fr01-24_PD24.mzML Mzml
PXP0425_KEAP1_Fr01-24_PD24.mzid.gz Mzid
PXP0425_KEAP1_Fr01_BLU2_2017_1465.raw Raw
PXP0425_KEAP1_Fr02_BLU2_2017_1466.raw Raw
PXP0425_KEAP1_Fr03_BLU2_2017_1467.raw Raw
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