PXD010568

PXD010568 is an original dataset announced via ProteomeXchange.

Title	Bruton’s Tyrosine Kinase Degradation as a Therapeutic Strategy for Cancer
Description	The covalent Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it also has off-target effects and multiple mechanisms of resistance, including the C481S mutation. We hypothesized that small molecule-induced BTK degradation might be able to overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in more durable suppression of signaling and proliferation in cancer cells than BTK inhibition and that BTK degraders are able to efficiently degrade BTK C481S. Moreover, we generated DD-03-171, an optimized lead compound that exhibits enhanced anti-proliferative effects on mantle cell lymphoma (MCL) cells in vitro as well as efficacy in a patient-derived xenograft model of MCL. These data suggest that targeted BTK degradation is an effective therapeutic approach in treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:47:06.281.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	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2018-07-26 01:44:16	ID requested
1	2019-01-25 07:58:40	announced
⏵ 2	2024-10-22 04:47:14	announced	2024-10-22: Updated project metadata.

Dobrovolsky D, Wang ES, Morrow S, Leahy C, Faust T, Nowak RP, Donovan KA, Yang G, Li Z, Fischer ES, Treon SP, Weinstock DM, Gray NS, Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood, 133(9):952-961(2019) [pubmed]

10.1182/blood-2018-07-862953;

curator keyword: Biomedical

submitter keyword: IMiDs, PROTAC , crl4,BTK, ubiquitin, cullin

Eric S. 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/2019/01/PXD010568

PRIDE project URI

• PRIDE
  1. PXD010568
     1. Label: PRIDE project
     2. Name: Bruton’s Tyrosine Kinase Degradation as a Therapeutic Strategy for Cancer