2. Academic Validation
  3. Photoaffinity Ligand of Cystic Fibrosis Corrector VX-445 Identifies SCCPDH as an Off-Target

Photoaffinity Ligand of Cystic Fibrosis Corrector VX-445 Identifies SCCPDH as an Off-Target

  • ACS Chem Biol. 2025 Jul 18;20(7):1560-1573. doi: 10.1021/acschembio.5c00157.
Minsoo Kim 1 2,  Kwangho Kim 1 3,  Jesun Lee 4,  Lea A Barny 1 2,  Toya D Scaggs 3,  Ian M Romaine 3,  KyuOk Jeon 3,  Simona G Codreanu 1 5,  Stacy D Sherrod 1 5,  John A McLean 1 5,  Anjaparavanda P Naren 4,  Gary A Sulikowski 1 3,  Lars Plate 1 6 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 2 Program in Chemical and Physical Biology, Vanderbilt University, Nashville, Tennessee 37240-0002, United States.
  • 3 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, California 90048, United States.
  • 5 Center for Innovative Technology, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 6 Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 7 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
PMID: 40539870 DOI: 10.1021/acschembio.5c00157
Abstract

Cystic fibrosis (CF) pharmacological correctors improve the cystic fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Several side effects of these correctors and adverse drug interactions have been reported, emphasizing the need to understand off-targets. We synthesized VU439, a functionalized photoaffinity ligand (PAL) of VX-445. Chemoproteomics analysis by mass spectrometry (MS) was used to identify cross-linked proteins in CF bronchial epithelial cells expressing F508del CFTR. We identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH), an uncharacterized putative oxidoreductase, as a VX-445-specific off-target. We also characterized changes in the metabolomic profiles of cells overexpressing SCCPDH to determine the consequence of binding of VX-445 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 the exacerbation of psychological symptoms observed in the clinic, thus emphasizing the need for further optimization of correctors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-174821
    Photoaffinity Ligand