PXD060898-1

PXD060898 is an original dataset announced via ProteomeXchange.

Title	Photoaffinity ligand of Cystic Fibrosis corrector VX-445 identifies SCCPDH as an off-target
Description	Cystic fibrosis (CF) pharmacological correctors such as VX-445 are used in combinations as highly effective modulator therapy (HEMT) at CF clinics due to their efficacy in improving Cystic Fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Yet, several side-effects from these correctors and adverse drug interactions have been reported, emphasizing the need to understand the etiology of these effects that potentially arise from off-targets. We synthesized VU439, a functionalized photoaffinity ligand (PAL) of VX-445 that harbors a diazirine-moiety for in situ photocrosslinking upon UV radiation and an alkyne handle for click chemistry modifications to visualize and enrich crosslinked proteins. The PAL probe retained corrector function with mild efficacy in improving CFTR trafficking and function. Chemoproteomics analysis by mass spectrometry (MS) was used to identify crosslinked proteins in CF bronchial epithelial cells expressing F508del CFTR, identifying saccharopine dehydrogenase-like oxidoreductase (SCCPDH), an uncharacterized putative oxidoreductase, as a VX-445 specific off-target. We then characterized changes in the metabolomic profiles of cells overexpressing SCCPDH to determine the consequence of VX-445 binding to SCCPDH. These data show dysregulation of amino acid metabolism and a potential inhibitory activity of VX-445 on SCCPDH. The identified off-target may explain exacerbation of psychological symptoms observed in patients on HEMT, thus emphasizing the need for further optimization of corrector combinations.
HostingRepository	PRIDE
AnnounceDate	2025-07-28
AnnouncementXML	Submission_2025-07-27_18:08:57.041.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Minsoo Kim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-17 19:22:00	ID requested
⏵ 1	2025-07-27 18:08:57	announced

10.1021/acschembio.5c00157;

Kim M, Kim K, Lee J, Barny LA, Scaggs TD, Romaine IM, Jeon K, Codreanu SG, Sherrod SD, McLean JA, Naren AP, Sulikowski GA, Plate L, Photoaffinity Ligand of Cystic Fibrosis Corrector VX-445 Identifies SCCPDH as an Off-Target. ACS Chem Biol, 20(7):1560-1573(2025) [pubmed]

submitter keyword: Elexacaftor,cystic fibrosis (CF), VU439, click chemistry, target identification, cystic fibrosis transmembrane conductance regulator (CFTR), off-target, mass spectrometry (MS), proteomics, diazirine, metabolomics, chemoproteomics, corrector, photoaffinity ligand (PAL), VX-445, saccharopine dehydrogenase-like oxidoreductase (SCCPDH)

Lars Plate
contact affiliation	Department of Chemistry, Vanderbilt University, Nashville, TN, United States
contact email	lars.plate@vanderbilt.edu
lab head
Minsoo Kim
contact affiliation	Vanderbilt University
contact email	min.soo.kim.1@vanderbilt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060898
     1. Label: PRIDE project
     2. Name: Photoaffinity ligand of Cystic Fibrosis corrector VX-445 identifies SCCPDH as an off-target