Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

SMARCA2/4 degradation tails mediate recruitment of two different E3 ligases 

ABSTRACT: In this work, we characterise novel SMARCA2/4 degraders using a robust cell biology and structural workflow and reveal for the first time, the recruitment of two E3 ligase substrate receptors: FBXO22 and DCAF16 by the same degradation tail. Furthermore, we were able to chemically fine-tune this dual ligase dependency dialling out DCAF16 providing insights into the mechanisms for DCAF16 and FBXO22 covalent recruitment. Dual ligase recruitment may serve to overcome E3 ligase acquired resistance that may feature with clinical use of degraders.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Gajanan Sathe

LAB HEAD: Alessio Ciulli

PROVIDER: PXD065445 | Pride | 2026-05-16

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	gene58_1.raw	Raw
	gene58_10.raw	Raw
	gene58_11.raw	Raw
	gene58_12.raw	Raw
	gene58_13.raw	Raw

Items per page:

1 - 5 of 23

Publications

Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation.

Spiteri Valentina A VA Segal Dmitri D Correa-Sáez Alejandro A Iso Kentaro K Casement Ryan R Muñoz I Ordoño Miquel M Nakasone Mark A MA Sathe Gajanan G Schätz Caroline C Peters Hannah E HE Doward Mark M Kainacher Lisa L Cowan Angus D AD Ciulli Alessio A Winter Georg E GE

Nature chemical biology 20260512

Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) target proteins for degradation by co-opting an E3 ligase. While heterotrivalent PROTACs that can recruit multiple E3 ligases have been described, all MGDs reported to date depend on a single E3. Using orthogonal genetic screening, biophysical and structural analyses, we show that a monovalent MGD can recruit CUL4<sup>DCAF16</sup> and CRL1<sup>FBXO22</sup> in parallel to degrade SMARCA2/4. Deep mutational scanning ident ...[more]

PMID: 42120501

Similar Datasets

SMARCA2/4 degradation tails mediate recruitment of two different E3 ligases 

Project description:In this work, we characterise novel SMARCA2/4 degraders using a robust cell biology and structural workflow and reveal for the first time, the recruitment of two E3 ligase substrate receptors: FBXO22 and DCAF16 by the same degradation tail. Furthermore, we were able to chemically fine-tune this dual ligase dependency dialling out DCAF16 providing insights into the mechanisms for DCAF16 and FBXO22 covalent recruitment. Dual ligase recruitment may serve to overcome E3 ligase acquired resistance that may feature with clinical use of degraders.

2026-05-16 | PXD065523 | Pride

Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept

Project description:Prospective discovery of molecular glues degraders for a specific therapeutic target protein of interest is an emerging strategy in drug discovery. Modification of pre-existing ligands with fragments that can alter the protein surface can lead to the creation of novel compounds (‘’targeted glues’’) able to induce neo-interactions between the target and an E3 ligase, resulting in targeted protein degradation. By screening a library of potential BRD9 targeted glue compounds, we have discovered a potent and selective, reversibly covalent BRD9 degrader, AMPTX-1. Co-immunoprecipitation-mass spectrometry experiments demonstrated that cell treatment with AMPTX-1 induces selective recruitment of BRD9 to the E3 ligase DCAF16. Degradation is dependent on the engagement of the surface Cys58 of DCAF16 and formation of a covalent adduct to DCAF16 is facilitated by the ternary complex formation with BRD9. BRD9 degradation is achieved in vivo after oral dosing, demonstrating that covalent recruitment of DCAF16 is a viable strategy for targeted protein degradation and can be achieved with drug-like, orally bioavailable compounds with promising in vivo activity.

2025-11-10 | PXD062355 | Pride

Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept

2025-11-10 | PXD062354 | Pride

Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation

Project description:Targeted Protein Degradation (TPD) utilizes small molecules to direct proteins towards E3 ubiquitin ligases for degradation, but is limited by the small number of ligases accessible for this approach. We introduce SP3N, a novel degrader targeting FKBP12, designed with a simple structure that integrates a FKBP12 ligand with a degradation-inducing alkylamine tail. Through comprehensive target identification, we show that SP3N acts as a prodrug, converting its alkylamine to an active aldehyde that engages the SCF FBXO22 ligase for FKBP12's degradation via covalent attachment to FBXO22's Cys326, essential for the degradation process. This mechanism, also applicable to NSD2 and XIAP degraders, presents a new, broadly applicable TPD method involving alkylamine-based tethering and covalent modification of FBXO22.

2024-06-24 | PXD049330 | Pride

Targeting FBXO22 enhances radiosensitivity of non-small cell lung cancer by inhibiting FOXM1/Rad51 axis

Project description:FBXO22 is the substrate recognition subunit of SCF E3 ubiquitin ligase, which plays an important role in the occurrence, development and therapeutic response of solid tumors.At present, the relationship between FBXO22 and radiosensitivity of lung cancer has not been fully elucidated.Here we present evidence to prove that abnormally expressed FBXO22 in lung cancer promotes transcriptional activation of homologous recombination enzyme Rad51 by up-regulating transcription factor FOXM1, which in turn induces radioresistance in lung cancer.By comparing with the reference data set of cMap database, Deguelin was identified as a small molecular inhibitor of FBXO22.Deguelin increases the radiosensitivity of lung cancer cells in vitro and in vivo in a FBXO22-dependent manner and is safely tolerated.This study revealed the identity of a novel radioresistance biomarker of FBXO22 and provided preclinical evidence for the clinical transformation of this target by screening small molecular inhibitors.

2024-02-07 | GSE235374 | GEO

BRD4 degradation via stabilization of a native interaction with DCAF16

Project description:Targeted protein degradation is a modality based on small molecules that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase, thus prompting POI ubiquitination and degradation. To expand the reach of TPD, current research is geared to unlock novel E3s. To that end, the transcriptional co-activator protein BRD4 has emerged as a frequently used POI. Derivatization of known BRD4 ligands with structurally diverse substituents has yielded a suite of potent BRD4 degraders, thus generating the notion that BRD4 is particularly amenable to TPD. Here, we mechanistically characterize two BRD4 degraders via orthogonal CRISPR screens. Despite their structural dissimilarity, both degraders functionally converge on a unifying mechanism of action that involves the CRL4DCAF16 ligase complex. Using recombinant reconstitution, as well as biophysical and structural elucidation, we demonstrate that BRD4 has an intrinsic activity for DCAF16, which is further enhanced by both compounds. We uncover a novel mode of molecular recognition based on multivalent "gluing" of BRD4 onto DCAF16 that requires both bromodomains of BRD4. Our data thus imply a substantial conceptual overlap between PROTACs and molecular glue degraders, and highlight multivalency as a novel concept in the design of proximity-inducing drugs.

2024-01-08 | PXD040570 | Pride

Biotinylated MMH2 pulldown LCMS

Project description:Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism. We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4-DCAF16 ligase to the second bromodomain of BRD4. To gain a deeper understanding into the potential off-target effects of more reactive degraders, we conducted streptavidin pulldowns of K562 lysate incubated with engineered MMH2-Biotin, a probe molecule that appends linker-biotin onto the second exit vector of MMH2.

2025-05-06 | PXD051457 | Pride

BromoCatch: a self-labelling tag platform for protein analysis and live cell imaging

Project description:Visualizing and manipulating proteins in live cells is crucial for studying complex biological processes. Self-labelling protein (SLP) tags such as HaloTag and SNAP-tag can be fused to genes of interest to allow protein labelling in cells. New tools to enable rapid, specific and stable protein labelling are in demand to expand the arsenal of SLPs. Here we present BromoCatch, a novel SLP platform based on a small ~13 kDa bromodomain (BD) engineered with a nucleophilic cysteine for covalent ligand engagement. A structure-based designed library of 16 “bumped” binders bearing diverse electrophilic warheads was screened against two cysteine mutants using differential scanning fluorimetry and intact protein mass spectrometry to monitor covalent complex formation. We qualify the para-acrylamide bumped derivative MR116 and the Brd4-BD2 double mutant L387A,E438C as the protein-ligand pair of choice, and its covalent binding mode was confirmed by an X-ray cocrystal structure solved to 1.3 Å of resolution. The BromoCatch platform exhibited potent and irreversible target engagement in cells using nanoBRET and residence time assays. Practicality and scope are further demonstrated through the design and proof-of-concept application of a biotinylated conjugate, PROTAC tag degraders, and fluorescent probes of both full-on and switch-on types for ex-cellulo and live-cell imaging, including side-by-side comparison and orthogonality with HaloTag. Together, we qualify BromoCatch as a novel, versatile and efficient protein labelling tool. Its advantageous design features and kinetic fitness enable modular attachment of diverse functionalities, multiplexing with other SLPs, and catalytic degradation, which will open future applications and witness broad utility.

2026-05-04 | PXD074567 | Pride

ChemBioID - An integrated chemical biology workflow for the investigation of proximity-induced pharmacology by the compound NVS-BPTF-1-B

Project description:Modulation of protein-protein interactions with small molecules represents an emerging area of interest in drug discovery, enabling new therapeutic paradigms unprecedented with other drug classes such as catalytic enzyme inhibitors. Immunomodulatory drugs are a prime example for proximity-induced pharmacology where in the case of multiple myeloma, degradation of oncogenic transcription factors is achieved via recruitment of an E3 ligase complex. Here, we present a streamlined workflow for profiling small molecule degraders, integrating proteomics-based techniques such as proximity labelling, in-cell interaction validation assays, ubiquitination analysis and protein degradation monitoring. Application of this combined approach to a set of degraders enabled us to identify known and novel IMiD-dependent CRBN binders, thereby revealing the extended recruitment capacity of these compounds and raising important questions about potential degrader pharmacology beyond the dogma of recruitment, ubiquitination and degradation. This project is part of the IMI EUbOPEN project.

2025-04-30 | PXD056164 | Pride

ChemBioID - An integrated chemical biology workflow for the investigation of proximity-induced pharmacology by the compound NVS-BPTF-A-2

2025-04-30 | PXD056314 | Pride