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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer

LAB HEAD: Eric Fischer

PROVIDER: PXD022059 | Pride | 2021-07-30

REPOSITORIES: Pride

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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 | PXD022021 | Pride

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

2021-07-30 | PXD022060 | 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 | PXD022022 | Pride

Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins

Project description:Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR/Cas9-based gene-editing studies. We observed that myeloma cell resistance to "degraders" of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; involves loss-of-function for the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for CRBN- vs. VHL-based degraders explains mechanistically the lack of cross-resistance for degraders targeting the same protein via different E3 ligase/CRLs.

2021-02-12 | GSE162205 | GEO

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 | PXD016168 | Pride

Reprogramming the E3 ubiquitin ligase CRL4CRBN to degrade Helios

2021-05-26 | PXD023691 | Pride

Exploring Effectiveness of KEAP1-based PROTAC Strategy

Project description:Targeted protein degradation (TPD) uses small molecules to recruit E3 ubiquitin ligases into proximity of proteins of interest, inducing ubiquitination-dependent degradation. A major bottleneck in the TPD field is the lack of accessible E3 ligase ligands for developing degraders. To expand the E3 ligase toolbox, we sought to convert the KEAP1 inhibitor KI696 into a recruitment handle for several targets. While we were able to generate KEAP1-recruiting degraders of BET family and murine FAK we discovered that the target scope of KEAP1 was narrow, as targets easily degraded by a cereblon (CRBN)-recruiting degrader were refractory to KEAP1-mediated degradation. Linking the KEAP1-binding ligand to a CRBN-binding ligand resulted in a molecule that induced degradation of KEAP1 but not CRBN. In sum, we characterize tool compounds to explore KEAP1-mediated ubiquitination and delineate the challenges of exploiting new E3 ligases for generating bivalent degraders.

2022-09-07 | PXD034424 | Pride

Exploring Effectiveness of KEAP1-based PROTAC Strategy

2022-09-07 | PXD034378 | Pride

Exploring Effectiveness of KEAP1-based PROTAC Strategy

2022-09-07 | PXD034423 | Pride