Photoaffinity ligand of Cystic Fibrosis corrector VX-445 identifies SCCPDH as an off-target

2025 · doi:10.1101/2025.02.22.639665
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The study synthesized VU439, a functionalized photoaffinity ligand of the cystic fibrosis drug corrector VX-445, and used chemoproteomics with mass spectrometry in CF bronchial epithelial cells expressing F508del CFTR to identify VX-445 binding partners. They identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH) as a specific, previously uncharacterized off-target and assessed functional consequences by profiling metabolomic changes in cells overexpressing SCCPDH. The authors found dysregulation of amino acid metabolism and suggested potential inhibitory activity of VX-445 on SCCPDH, noting that this off-target may relate to reported exacerbation of psychological symptoms in clinical settings. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Cystic fibrosis (CF) pharmacological correctors improve Cystic Fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Several side-effects from 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 crosslinked 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 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 the clinic, thus emphasizing the need for further optimization of correctors.
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Abstract Cystic fibrosis (CF) pharmacological correctors improve Cystic Fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Several side-effects from 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 crosslinked 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 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 the clinic, thus emphasizing the need for further optimization of correctors. Competing Interest Statement The authors have declared no competing interest.

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