Developing Isoxazole as a Native Photo-Cross-Linker for Photoaffinity Labeling and Chemoproteomics

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Detail(s)

Original languageEnglish
Article numbere202209947
Journal / PublicationAngewandte Chemie - International Edition
Volume61
Issue number47
Online published23 Sept 2022
Publication statusPublished - 21 Nov 2022

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Abstract

Photoaffinity labeling is a powerful technique to interrogate drug-protein interactions in native cellular environments. Photo-cross-linkers are instrumental for this technique. However, the introduction of unnatural photo-cross-linkers may significantly reduce the bioactivity of the drug, thus impairing the chemoproteomic outcomes. Herein, we developed a common pharmacophore, isoxazole, into a natively embedded photo-cross-linker for chemoproteomics, which minimally perturbs the drug structure. The photo-cross-linking reactions of the isoxazole were thoroughly investigated for the first time. Functionalized isoxazoles were then designed and applied to protein labeling, demonstrating the superior photo-cross-linking efficiency. Subsequently, two isoxazole-based drugs, Danazol and Luminespib, were employed in chemoproteomic studies, revealing their potential cellular targets. These results provide valuable strategies for future chemoproteomic study and drug development.

Research Area(s)

  • Chemoproteomics, Drug Discovery, Isoxazole, Photo-Cross-Linker, Photoaffinity Labeling

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