PXD003373-2

PXD003373 is an original dataset announced via ProteomeXchange.

Title	Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors
Description	Protein 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.
HostingRepository	PRIDE
AnnounceDate	2017-03-22
AnnouncementXML	Submission_2017-03-22_01:46:32.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Susan Klaeger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2015-12-18 00:51:03	ID requested
1	2016-02-19 08:23:56	announced
⏵ 2	2017-03-22 01:46:46	announced	Updated project metadata.
3	2024-10-22 04:28:12	announced	2024-10-22: Updated project metadata.

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]

curator keyword: Biological, Biomedical

submitter keyword: chemical proteomics, Kinobeads, Ferrochelatase, FECH, kinase inhibitor, photosensitivity, Vemurafenib

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics, Technische Universität München, Germany
contact email	kuster@tum.de
lab head
Susan Klaeger
contact affiliation	Chair of Proteomics and Bioanalytics, TUM
contact email	Susan.Klaeger@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD003373
     1. Label: PRIDE project
     2. Name: Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors