PXD055068-1

PXD055068 is an original dataset announced via ProteomeXchange.

Title	High-throughput chemical diversification to discover chemical inducers of proximity
Description	Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing a privileged rewiring of cellular biochemistry. We hypothesized that high-throughput chemical synthesis could be used to alter the composite surface topology of a protein-ligand complex at scale, allowing for the prospective discovery of structural modifications that transform a ligand into a CIP. Selecting a ligand for the transcriptional co-activator, ENL, as proof of concept, we synthesized 3,163 analogs in parallel and then screened each for the acquired ability to induce ENL degradation. This effort revealed a pyrrolidine spirosuccinimide-bearing analog, dHTC1, that elicits potent, selective, and stereochemistry-dependent degradation of ENL in vitro and in vivo. Further study revealed that dHTC1 functions through CRL4CRBN, the ubiquitin ligase complex responsible for the therapeutic effects of thalidomide analogs, despite possessing minimal intrinsic affinity for the ligase. Instead, binding to ENL templates a projection of its spirosuccinimide group that allows the ENL:dHTC1 complex to bind CRL4CRBN with high affinity and cooperativity, leveraging a distributed interface of ENL-CRBN interactions. Extending this chemistry to identify BRD4 degraders, we altogether present a facile method to prospectively transform ligands into chemical inducers of proximity and, by revealing a new mechanism to elicit CRL4CRBN-dependent degradation, point toward an expanded chemical space to coopt this therapeutically important ubiquitin ligase complex.
HostingRepository	PRIDE
AnnounceDate	2026-02-10
AnnouncementXML	Submission_2026-02-10_11:17:28.787.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jamie Shaum
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-22 06:13:08	ID requested
⏵ 1	2026-02-10 11:17:29	announced

10.1038/S41589-025-02137-2;

ProteomeXchange project tag: Human Proteome Project

submitter keyword: proteomics,targeted protein degradation, molecular glue

Michael Erb, PhD
contact affiliation	The Scripps Research Institute, Department of Chemistry
contact email	michaelerb@scripps.edu
lab head
Jamie Shaum
contact affiliation	The Scripps Research Institute
contact email	jshaum@scripps.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/02/PXD055068

PRIDE project URI

• PRIDE
  1. PXD055068
     1. Label: PRIDE project
     2. Name: High-throughput chemical diversification to discover chemical inducers of proximity