Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Redirecting the neo-substrate specificity of Cereblon-targeting PROTACs to Helios

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Eric Fischer

LAB HEAD: Eric Fischer

PROVIDER: PXD036170 | Pride | 2022-09-07

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	checksum.txt	Txt
	esf_5594.raw	Raw
	esf_5595.raw	Raw
	esf_5596.raw	Raw
	esf_5597.raw	Raw

Items per page:

1 - 5 of 26

Similar Datasets

Reprogramming the E3 ubiquitin ligase CRL4CRBN to degrade Helios

Project description:The zinc finger transcription factor Helios is critical for maintaining the identity and suppressive phenotype of regulatory T cells (Tregs) and as such is an attractive target to enhance the efficacy of currently approved immunotherapies. However, no small molecules exist which can directly modulate Helios activity or abundance. Here, we report the structure-guided development of novel small molecules capable of inducing neo-interactions between Helios and the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN), thereby promoting Helios degradation. Crystallographic studies reveal that these new compounds accommodate a key histidine residue in the β-hairpin loop of its second zinc finger domain. Finally, pharmacological Helios degradation destabilized the anergic phenotype of regulatory T cells, demonstrating that Helios is a new druggable target that may enhance anti-tumor immunity. Our study provides a road-map for developing small molecule degraders of other difficult-to-drug targets through ligase reprogramming that is complementary to the bi-valent proteolysis targeting chimera (PROTACs) approach.

2021-05-26 | PXD023691 | Pride

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

Project 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.

2023-12-18 | PXD046286 | Pride

Reprogramming the E3 ubiquitin ligase CRL4CRBN to degrade Helios

2021-05-26 | PXD016168 | Pride

A degron blocking strategy towards improved CRBN recruiting PROTAC selectivity

Project description:The different layers of complexity in PROTAC design have slowed the broad implementation of this novel pharmacological approach. Given the challenges and opportunities of CRL4CRBN hijacking PROTACs we set out to identify and develop broadly implementable strategies to generate PROTACs with improved specificity for their targets. We used structural analysis of known neo-substrate degrons to generate “degron blocked IMiD” analogues and validated that they did not degrade any known neo-substrates using quantitative proteomics. We then applied this strategy to a known BRD9 PROTAC (dBRD9-A) to generate a degron-blocking analogue with a specific degradation profile.

2023-07-10 | PXD038298 | Pride

A degron blocking strategy towards improved CRBN recruiting PROTAC selectivity

2023-07-10 | PXD038503 | Pride

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

Project 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.

2023-12-18 | PXD047347 | Pride

Chemically induced cereblon (CRBN) degradation: efficacy of recruiting CRBN in comparison to VHL

Project description:As small molecule degrader technology has developed, it has raised the question of whether E3 ligases could be induced to self-ubiquitinate. To examine this question, we generated six CRBN-CRBN degraders (also referred to as homo-PROTACs) and six CRBN-VHL degraders (hetero-PROTACs). From these compounds we identified two potent and selective CRBN degraders (ZXH-4-130 and ZXH-4-137), both of which are CRBN-VHL compounds. Comparison of these compounds to previously reported small molecule CRBN degraders further validated our observation that CRBN-VHL compounds are more potent degraders of CRBN than CRBN-CRBN compounds.

2021-07-30 | PXD022060 | Pride

Chemically induced cereblon (CRBN) degradation: efficacy of recruiting CRBN in comparison to VHL

2021-07-30 | PXD022021 | Pride

Chemically induced cereblon (CRBN) degradation: efficacy of recruiting CRBN in comparison to VHL

2021-07-30 | PXD022058 | Pride

Chemically induced cereblon (CRBN) degradation: efficacy of recruiting CRBN in comparison to VHL

2021-07-30 | PXD022059 | Pride