PXD012963

PXD012963 is an original dataset announced via ProteomeXchange.

Title	Divergent polypharmacology-driven cellular activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets: IMAC Phosphoproteomics
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_09:13:10.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD012963
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; TMT6plex; Oxidation; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-03-05 03:00:38	ID requested
⏵ 1	2019-06-24 09:13:11	announced

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: Polypharmacology, Foretinib, Cabozantinib, Lung Cancer, IMAC, Phosphoproteomics

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

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/2019/06/PXD012963

PRIDE project URI

• PRIDE
  1. PXD012963
     1. Label: PRIDE project
     2. Name: Divergent polypharmacology-driven cellular activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets: IMAC Phosphoproteomics