PXD015513 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Development and Characterization of a Wee1 Kinase Degrader |
Description | The G1/S cell-cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells particularly reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Inhibiting regulators of the G2/M checkpoint can therefore drive cancer cells into premature mitosis, ultimately causing cell death by mitotic catastrophe. One such regulator is Wee1, a nuclear tyrosine kinase that delays mitotic entry by phosphorylating CDK1 at Tyr15. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose- limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we designed small molecule degraders of Wee1 by conjugating AZD1775 to the cereblon (CRBN)- binding ligand, pomalidomide, as informed by molecular docking. The resulting lead compound, ZNL- 02-096, degrades Wee1 while sparing PLK1, induces G2/M phase accumulation at up to 10-fold lower concentrations than AZD1775, and potently synergizes with Olaparib in ovarian cancer cell lines. We demonstrate that ZNL-02-096 has CRBN-dependent pharmacology that is distinct from the conventional catalytic inhibitor, AZD1775, which justifies further evaluation of selective Wee1 degraders. |
HostingRepository | PRIDE |
AnnounceDate | 2019-11-18 |
AnnouncementXML | Submission_2020-01-14_06:51:39.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; phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2019-09-19 08:34:00 | ID requested | |
1 | 2019-11-18 01:24:44 | announced | |
⏵ 2 | 2020-01-14 06:51:40 | announced | 2020-01-14: Updated publication reference for PubMed record(s): 31735695. |
Publication List
Li Z, Pinch BJ, Olson CM, Donovan KA, Nowak RP, Mills CE, Scott DA, Doctor ZM, Eleuteri NA, Chung M, Sorger PK, Fischer ES, Gray NS, Development and Characterization of a Wee1 Kinase Degrader. Cell Chem Biol, 27(1):57-65.e9(2020) [pubmed] |
Keyword List
submitter keyword: Wee1, cancer, PROTAC, CRBN, ubiquitin, crl4 |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD015513
- Label: PRIDE project
- Name: Development and Characterization of a Wee1 Kinase Degrader