PXD012962 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Divergent polypharmacology-driven cellular activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets: Tyrosine Phosphorylation |
Description | Despite recent successes of precision and immunotherapies there is a persisting need for novel targeted or multi-targeted approaches in complex diseases. Through a systems pharmacology approach including phenotypic screening, chemical and phosphoproteomics and RNA-Seq, we elucidated the targets and mechanisms underlying the differential anticancer activity of two structurally related multi-kinase inhibitors, foretinib and cabozantinib, in lung cancer cells. Biochemical and cellular target validation using probe molecules and RNA interference revealed a polypharmacology mechanism involving MEK1/2, FER and AURKB, which were each more potently inhibited by foretinib than cabozantinib. Based on this, we developed a synergistic combination of foretinib with barasertib, a more potent AURKB inhibitor, for MYC-amplified small cell lung cancer. This systems pharmacology approach showed that small structural changes of drugs can cumulatively, through multiple targets, result in pronounced anticancer activity differences and that detailed mechanistic understanding of polypharmacology can enable repurposing opportunities for cancers with unmet medical need. |
HostingRepository | PRIDE |
AnnounceDate | 2019-06-24 |
AnnouncementXML | Submission_2019-06-24_08:52:36.xml |
DigitalObjectIdentifier | https://dx.doi.org/10.6019/PXD012962 |
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 | Phospho; Oxidation; Carbamidomethyl |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2019-03-05 03:00:26 | ID requested | |
⏵ 1 | 2019-06-24 08:52:37 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
curator keyword: Biomedical |
submitter keyword: Polypharmacology, Foretinib, Cabozantinib, Lung Cancer, Phosphotyrosine |
Contact List
Uwe Rix, PhD |
contact affiliation | Drug Discovery Moffitt Cancer Center Tampa, FL, USA |
contact email | uwe.rix@moffitt.org |
lab head | |
John Koomen |
contact affiliation | Moffitt Cancer Center |
contact email | john.koomen@moffitt.org |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD012962
- Label: PRIDE project
- Name: Divergent polypharmacology-driven cellular activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets: Tyrosine Phosphorylation