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

Authors：Cheng, Ke; Qi, Junyang; Ren, Xiaojie; Zhang, Jie; Li, Huangxu; Xiao, Hanyue; Wang, Rui; Liu, Zhiyang; Meng, Lingkuan; Ma, Nan^*; Sun, Hongyan^*

Source：Angewandte Chemie - International Edition, 2022, 61(47).

DOI：10.1002/anie.202209947

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

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.

• Institution
  中山大学