PXD055398

PXD055398 is an original dataset announced via ProteomeXchange.

Title	A Kinetic Scout Approach Accelerates Targeted Protein Degrader Discovery
Description	Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharmaceutical industry, leading to an intensive focus on strategies that can accelerate their identification and optimization. We and others have previously used chemical proteomics to map degradable target space, and these datasets have been used to develop and train multiparameter models to extend degradability predictions across the proteome. In this study, we now turn our attention to develop generalizable chemistry strategies to accelerate the development of new bifunctional degraders. We implement lysine-targeted reversible-covalent chemistry to rationally tune the binding kinetics at the protein-of-interest across a set of 25 targets. We define an unbiased workflow consisting of global proteomics analysis, IP/MS of ternary complexes and the E-STUB assay, to mechanistically characterize the effects of ligand residence time on targeted protein degradation and formulate hypotheses about the rate-limiting step of degradation for each target. Our key finding is that target residence time is a major determinant of degrader activity, and this can be rapidly and rationally tuned through the synthesis of a minimal number of analogues to accelerate early degrader discovery and optimization efforts.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_07:53:57.722.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-30 11:02:48	ID requested
⏵ 1	2025-05-06 07:53:58	announced

10.1002/anie.202417272;

Fan AT, Gadbois GE, Huang HT, Chaudhry C, Jiang J, Sigua LH, Smith ER, Wu S, Poirier GJ, Dunne-Dombrink K, Goyal P, Tao AJ, Sellers WR, Fischer ES, Donovan KA, Ferguson FM, A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development. Angew Chem Int Ed Engl, 64(5):e202417272(2025) [pubmed]

submitter keyword: targeted protein degradation,PROTAC, degraders, kinase, vhl, ubiquitin, kinetics

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.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/2025/05/PXD055398

PRIDE project URI

• PRIDE
  1. PXD055398
     1. Label: PRIDE project
     2. Name: A Kinetic Scout Approach Accelerates Targeted Protein Degrader Discovery