PXD062355

PXD062355 is an original dataset announced via ProteomeXchange.

Title	Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept
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.
HostingRepository	PRIDE
AnnounceDate	2025-11-10
AnnouncementXML	Submission_2025-11-09_16:11:48.864.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Liliana Greger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-28 10:23:53	ID requested
⏵ 1	2025-11-09 16:11:49	announced

Hughes SJ, Stec WJ, Davies CTR, McGarry D, Williams A, Carrara M, Del Barco Barrantes I, Harris R, Tasegian A, Owens DDG, Fawcett A, Hellicar J, Azevedo A, Meier GP, Runcie AC, Greger L, O'Rourke M, Churcher I, Pass M, Brown GA, Ciulli A, Modis LK, Testa A, Mode of action of a DCAF16-recruiting targeted glue that can selectively degrade BRD9. Nat Commun, 16(1):8516(2025) [pubmed]

10.1038/s41467-025-63594-w;

submitter keyword: TMT,HEK293 IP-MS

Louise Modis
contact affiliation	Amphista Therapeutics Cambridge United Kingdom
contact email	louise.modis@amphista.com
lab head
Liliana Greger
contact affiliation	Amphista Therapeutics
contact email	liliana.greger@amphista.com
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/2025/11/PXD062355

PRIDE project URI

• PRIDE
  1. PXD062355
     1. Label: PRIDE project
     2. Name: Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept