PXD047934-2

PXD047934 is an original dataset announced via ProteomeXchange.

Title	Confounding factors in targeted degradation of short-lived proteins
Description	Targeted proTargeted protein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but it has not been systematically explored to what extent it influences target protein degradation. Using mathematical modelling of protein degradation, we demonstrate that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a PROTAC which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required before concluding that a novel agent works as a bone-fide targeted protein degrader. tein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but it has not been systematically explored to what extent it influences target protein degradation. Using mathematical modelling of protein degradation, we demonstrate that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a PROTAC which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required before concluding that a novel agent works as a bone-fide targeted protein degrader.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_07:00:14.432.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Vesna Vetma
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-19 02:59:15	ID requested
1	2024-10-01 09:31:10	announced
⏵ 2	2024-10-22 07:00:14	announced	2024-10-22: Updated project metadata.

10.1021/ACSCHEMBIO.4C00152;

submitter keyword: PROTAC. short-lived proteins, cancer, CRAF

Alessio Ciulli
contact affiliation	Centre for Targeted Protein Degradation, Dundee, UK
contact email	a.ciulli@dundee.ac.uk
lab head
Vesna Vetma
contact affiliation	University of Dundee
contact email	v.vetma@dundee.ac.uk
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/2024/10/PXD047934

PRIDE project URI

• PRIDE
  1. PXD047934
     1. Label: PRIDE project
     2. Name: Confounding factors in targeted degradation of short-lived proteins