PXD053505

PXD053505 is an original dataset announced via ProteomeXchange.

Title	Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K
Description	The CDK12 inhibitor, SR-4835, promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the de novo design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation, paving the way for more precise and effective therapeutic strategies in cancer treatment.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-06_20:41:37.750.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD053505
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-28 15:57:09	ID requested
⏵ 1	2025-05-06 20:41:38	announced

10.1039/d4cb00190g;

Ghosh P, Schmitz M, Pandurangan T, Zeleke ST, Chan SC, Mosior J, Sun L, Palve V, Grassie D, Anand K, Frydman S, Roush WR, Sch, ö, nbrunn E, Geyer M, Duckett D, Monastyrskyi A, Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K. RSC Chem Biol, 6(1):36-55(2024) [pubmed]

10.6019/PXD053505;

submitter keyword: CDK12, Molecular Glue Degraders,Cyclin K

Andrii Monastyrskyi
contact affiliation	Drug Discovery Moffitt Cancer Center Tampa, FL, USA
contact email	andrii.monastyrskyi@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
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/PXD053505

PRIDE project URI

• PRIDE
  1. PXD053505
     1. Label: PRIDE project
     2. Name: Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K