PXD041836

PXD041836 is an original dataset announced via ProteomeXchange.

Title	Design principles for cyclin K molecular glue degraders
Description	Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. To investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical, and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:06:04.863.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Hordeum vulgare (Barley); NCBI TaxID: 4513;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-26 15:46:32	ID requested
1	2023-10-19 17:14:22	announced
⏵ 2	2023-11-14 09:06:09	announced	2023-11-14: Updated project metadata.

Kozicka Z, Suchyta DJ, Focht V, Kempf G, Petzold G, Jentzsch M, Zou C, Di Genua C, Donovan KA, Coomar S, Cigler M, Mayor-Ruiz C, Schmid-Burgk JL, H, ä, ussinger D, Winter GE, Fischer ES, S, ł, abicki M, Gillingham D, Ebert BL, Thom, ä NH, Design principles for cyclin K molecular glue degraders. Nat Chem Biol, 20(1):93-102(2024) [pubmed]

submitter keyword: Ubiquitin, cdk12, molecular glue, cr8, cyclink, degrader

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/2023/10/PXD041836

PRIDE project URI

• PRIDE
  1. PXD041836
     1. Label: PRIDE project
     2. Name: Design principles for cyclin K molecular glue degraders