PXD071390

PXD071390 is an original dataset announced via ProteomeXchange.

Title	Covalent Reprogramming of Kinase Binders to Modulate Protein Homeostasis
Description	Small molecules that modulate protein abundance through induced proximity have expanded the landscape beyond traditional inhibition. Here, we explore how introducing covalent or latent electrophilic groups into a multi-kinase binder scaffold can reprogram protein homeostasis within the kinase family. Using the broad-spectrum kinase ligand TL13-87 as a template, we synthesized analogs bearing α-chloroacetamide, acrylamide, or terminal amine groups. Quantitative proteomics revealed that while most analogs had minimal global impact, MKI-AA uniquely stabilized the mitotic kinase AURKA, a protein often destabilized by ATP-competitive inhibitors. Mechanistic studies showed that MKI-AA acts post-translationally to suppress AURKA ubiquitination and proteasomal degradation. Proteomic mapping of MKI-AA-induced AURKA interactors revealed changes in protein associations upon treatment, providing potential mechanistic insights into how MKI-AA influences AURKA stability. Intriguingly, adding a short linker to MKI-AA converted it from a stabilizer into a degrader, highlighting how subtle structural variations can invert functional outcomes. These findings demonstrate that electrophilic ligand design can modulate kinase stability and reveal a previously unrecognized mode of covalent proximity-driven protein stabilization.
HostingRepository	PRIDE
AnnounceDate	2026-04-03
AnnouncementXML	Submission_2026-04-02_16:42:53.103.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaoyu Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-29 14:42:45	ID requested
⏵ 1	2026-04-02 16:42:53	announced

10.1002/ADVS.75153;

submitter keyword: Protein Stabilizers, Kinases, Protein Degraders,Proteomics, Enzymes

Xiaoyu Zhang
contact affiliation	Northwestern University, Department of Chemistry
contact email	zhang@northwestern.edu
lab head
Xiaoyu Zhang
contact affiliation	Northwestern University
contact email	zhang@northwestern.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD071390
     1. Label: PRIDE project
     2. Name: Covalent Reprogramming of Kinase Binders to Modulate Protein Homeostasis