⮝ Full datasets listing

PXD003373

PXD003373 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleChemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors
DescriptionProtein kinases are key components in signal transduction pathways and are established drug targets in oncology. Consequently, small molecule kinase inhibitors are on the rise but often show a rather broad target spectrum, potentially leading to toxic side effects. As a result, a broad assessment of the target space is desirable for proper interpretation of observed biological effects. The enzyme Ferrochelatase (FECH), which catalyzes the conversion of protoporphyrin IX into heme, was recently found to be an off-target of the BRAF inhibitor Vemurafenib potentially explaining the often severe phototoxicity associated with this drug in melanoma patients. However, the extent to which kinase inhibitors bind to FECH in general is currently unclear. Here, we used a chemical proteomics approach based on the kinobead technology to profile 226 clinical kinase inhibitors for their potential to bind FECH. Surprisingly, low or sub-micromolar FECH binding was detected for 29 (13%) of all compounds tested and isothermal dose response measurements confirmed drug binding to FECH in cells. We also show that Vemurafenib, Linsitinib, Neratinib and MK-2461 reduce heme levels in K562 cells, verifying that drug binding leads to loss of FECH activity. Further experiments identified the protoporphyrin pocket in FECH as one major binding site for small molecule inhibitors. Since genetic loss of FECH function leads to photosensitivity in humans, we suggest that FECH inhibition by kinase inhibitors is the molecular mechanism triggering photosensitivity in patients and should therefore be part of the pre-clinical tox package for kinase inhibitors.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_04:28:04.066.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSusan Klaeger
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue
InstrumentLTQ Orbitrap Elite
Dataset History
RevisionDatetimeStatusChangeLog Entry
02015-12-18 00:51:03ID requested
12016-02-19 08:23:56announced
22017-03-22 01:46:46announcedUpdated project metadata.
32024-10-22 04:28:12announced2024-10-22: Updated project metadata.
Publication List
10.1021/acschembio.5b01063;
Klaeger S, Gohlke B, Perrin J, Gupta V, Heinzlmeir S, Helm D, Qiao H, Bergamini G, Handa H, Savitski MM, Bantscheff M, M, é, dard G, Preissner R, Kuster B, Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors. ACS Chem Biol, 11(5):1245-54(2016) [pubmed]
Keyword List
curator keyword: Biological, Biomedical
submitter keyword: kinase inhibitor, FECH, photosensitivity,chemical proteomics, Ferrochelatase, Vemurafenib, Kinobeads
Contact List
Bernhard Kuster
contact affiliationChair of Proteomics and Bioanalytics, Technische Universität München, Germany
contact emailkuster@tum.de
lab head
Susan Klaeger
contact affiliationChair of Proteomics and Bioanalytics, TUM
contact emailSusan.Klaeger@tum.de
dataset submitter
Full Dataset Link List
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/2017/03/PXD003373
PRIDE project URI
Repository Record List
[ + ]