Acute pharmacological degradation of Helios destabilizes regulatory T cells

Wang, Eric S.; Verano, Alyssa; Nowak, Radosław P.; Yuan, Jingting; Donovan, Katherine A.; Eleuteri, Nicholas A.; Yue, Hong; Ngo, Kenneth; Lizotte, Patrick H.; Gokhale, Prafulla C.; Gray, Nathanael S.; Fischer, Eric S.

doi:10.1038/s41589-021-00802-w

Cited by 75 publications

(77 citation statements)

References 39 publications

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“…However, IKZF1 and 3 are broadly expressed in the developing and differentiated immune system and their degradation causes pleiotropic effects 9 . Our studies with DKY709 extend previous work using IMiD analogs capable of degrading IKZF2/4 along with IKZF1/3, which have the potential for confounding effects derived from co-degradation of IKZF1 and IKZF3 34 . In addition to effects in Tregs, this work supports a functional role for IKZF2/4 on Teff cell dysfunction, validating several published reports describing the expression of IKZF2 in dysfunctional Teff cells states 13,14,38 .…”

Section: Discussionsupporting

confidence: 74%

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Targeted degradation of IKZF2 for cancer immunotherapy

Solomon

Bonazzi

d’Hennezel

et al. 2022

Preprint

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Growing malignant tumors must evade destruction by the immune system, a hurdle some malignancies overcome by attracting immune-suppressive regulatory T-cells (Tregs)1. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Tregs, and IKZF2 deficiency enhances immune responses to tumors in mice2, suggesting IKZF2 may be an attractive target for cancer immunotherapy. Here we describe the discovery and characterization of DKY709, the first molecular glue degrader of IKZF2/4 which spares IKZF1/3. DKY709 was identified through a recruitment-guided medicinal chemistry campaign that redirected the degradation selectivity of CRBN binders towards IKZF2. The IKZF transcription factor selectivity of DKY709 was rationalized by the X-ray structure of the CRBN-DKY709-IKZF2(ZF2) ternary complex. Upon exposure to DKY709, human Tregs showed reduced suppressive activity and exhausted T-effector cells recovered IFNγ production. In vivo, oral treatment with DKY709 drove a rapid and sustained degradation of IKZF2 including in humans and led to delayed tumor growth in mice with humanized immune systems and enhanced immunization responses in monkeys. DKY709 is a first-in-class, potent and selective oral IKZF2/4 degrader currently being investigated in a phase 1 clinical trial as an immune-enhancing agent for cancer immunotherapy.

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Section: Discussionsupporting

confidence: 74%

“…2c). Unlike the recently published CRBN:IKZF2(ZF2) structure 34 , CRBN was bound to DKY709:IKZF2(ZF2) in the "open" conformation similarly to the CRBN-IKZF1(ZF2) complex 25 where the IMiD-binding domain (IBD) rotates ~45 degrees relative to the rest of the complex (Extended Data Fig. 2c).…”

Section: Biophysical and Structural Characterizationmentioning

confidence: 65%

Targeted degradation of IKZF2 for cancer immunotherapy

Solomon

Bonazzi

d’Hennezel

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This IKZF2 degradation is blocked after pretreatment of MLN4924, a neddylation inhibitor of the cullin scaffold in E3 ligases indicating that IKZF2 is a CC-92480 dependent substrate of CUL4 CRBN ligase. Recent studies have shown that IKZF2 degraders (ALV2 and DKY709) can modulate regulatory T-cells activity 58 (clinical trial #NCT03891953). This indicates that compounds with no activity in phenotypic viability screens may provide novel insights when included in degrader target screening in different cell contexts.…”

Section: Resultsmentioning

confidence: 99%

SimPLIT: Simplified Sample Preparation for Large-Scale Isobaric Tagging Proteomics

et al. 2022

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Large scale proteomic profiling of cell lines can reveal molecular signatures attributed to variable genotypes or induced perturbations, enabling proteogenomic associations and elucidation of pharmacological mechanisms of action. Although isobaric labeling has increased the throughput of proteomic analysis, the commonly used sample preparation workflows often require time-consuming steps and costly consumables, limiting their suitability for large scale studies. Here, we present a simplified and cost-effective one-pot reaction workflow in a 96-well plate format (SimPLIT) that minimizes processing steps and demonstrates improved reproducibility compared to alternative approaches. The workflow is based on a sodium deoxycholate lysis buffer and a single detergent cleanup step after peptide labeling, followed by quick off-line fractionation and MS2 analysis. We showcase the applicability of the workflow in a panel of colorectal cancer cell lines and by performing target discovery for a set of molecular glue degraders in different cell lines, in a 96-sample assay. Using this workflow, we report frequently dysregulated proteins in colorectal cancer cells and uncover cell-dependent protein degradation profiles of seven cereblon E3 ligase modulators (CRL4 CRBN ). Overall, SimPLIT is a robust method that can be easily implemented in any proteomics laboratory for medium-to-large scale TMT-based studies for deep profiling of cell lines.

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“…Foxp3 , the transcription factor that specifies the Treg cell lineage, essential for Treg cell differentiation and suppressor function and defines the Treg cell lineage 65, 66 . Helios ( IKZF2 ) belongs to the Ikaros transcription factor family, is found critically required to maintain a stable Treg cell phenotype in the inflammatory diseases in recent years 67 . To be noted, studies indicated Helios enhances regulatory T cell function in cooperation with Foxp3 in patients with rheumatoid arthritis 68 .…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor combined with aspirin displays the signature of regulating the gut microbiome in consistence with improving the immuno-inflammatory response in atherosclerosis

Bai

Zhang

Liu

et al. 2022

Preprint

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Experiment implicated ticagrelor, one of the P2Y12 inhibitors, exerted antibacterial activity against gram-positive bacteria established from clinical evidence that it could reduce the incidence of infection-related disease. Here we performed 16S rRNA and metagenomic analysis from patients with unstable angina pectoris (UAP) treated with ticagrelor plus aspirin or clopidogrel plus aspirin for one month to determine the composition and functions of the gut microbiome difference between the two main medications. Our results suggested that the functional peptidoglycan and Staphylococcus aureus infection biosynthesis pathways were downregulated with ticagrelor-aspirin treatment in the gut. Furthermore, we found these changes were accompanied by increasing peripheral regulatory T cells (Tregs) and ectonucleotidases CD39/CD73 expressions with responding to ameliorating inflammation. To further validate the result, 16S rRNA and metabolomic analysis were carried out upon Western-diet (WD)-fed ApoE-/- mice, we found mice treated with ticagrelor plus aspirin exerted optimal synergistic effects on reducing the plaque burden and ameliorating inflammation through altered composition and functions of the gut microbiome which keeping in line with our clinical findings.

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Acute pharmacological degradation of Helios destabilizes regulatory T cells

Cited by 75 publications

References 39 publications

Targeted degradation of IKZF2 for cancer immunotherapy

Targeted degradation of IKZF2 for cancer immunotherapy

SimPLIT: Simplified Sample Preparation for Large-Scale Isobaric Tagging Proteomics

Ticagrelor combined with aspirin displays the signature of regulating the gut microbiome in consistence with improving the immuno-inflammatory response in atherosclerosis

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