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

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

doi:10.1002/anie.202209947

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

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

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

27 Citations (Scopus)

122 Downloads (CityUHK Scholars)

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.

Original language	English
Article number	e202209947
Journal	Angewandte Chemie - International Edition
Volume	61
Issue number	47
Online published	23 Sept 2022
DOIs	https://doi.org/10.1002/anie.202209947
Publication status	Published - 21 Nov 2022

Funding

The authors thank the financial support from the National Natural Science Excellent Young Scientists Fund of China (Hong Kong and Macau) (Grant No. 32122003), Research Grants Council of Hong Kong (Grant Nos. 11302320 and 11305221). We thank Prof. Deng Wenbin for his invaluable suggestions on this work

Research Keywords

Chemoproteomics
Drug Discovery
Isoxazole
Photo-Cross-Linker
Photoaffinity Labeling

Publisher's Copyright Statement

COPYRIGHT TERMS OF DEPOSITED POSTPRINT FILE: This is the peer reviewed version of the following article: Cheng, K., Qi, J., Ren, X., Zhang, J., Li, H., Xiao, H., Wang, R., Liu, Z., Meng, L., Ma, N., & Sun, H. (2022). Developing Isoxazole as a Native Photo-Cross-Linker for Photoaffinity Labeling and Chemoproteomics. Angewandte Chemie - International Edition, 61(47), [e202209947], which has been published in final form at https://doi.org/10.1002/anie.202209947.
This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

RGC Funding Information

RGC-funded

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title = "Developing Isoxazole as a Native Photo-Cross-Linker for Photoaffinity Labeling and Chemoproteomics",

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.",

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author = "Ke Cheng and Junyang Qi and Xiaojie Ren and Jie Zhang and Huangxu Li and Hanyue Xiao and Rui Wang and Zhiyang Liu and Lingkuan Meng and Nan Ma and Hongyan Sun",

year = "2022",

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AU - Cheng, Ke

AU - Qi, Junyang

AU - Ren, Xiaojie

AU - Zhang, Jie

AU - Li, Huangxu

AU - Xiao, Hanyue

AU - Wang, Rui

AU - Liu, Zhiyang

AU - Meng, Lingkuan

AU - Ma, Nan

AU - Sun, Hongyan

PY - 2022/11/21

Y1 - 2022/11/21

N2 - 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.

AB - 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.

KW - Chemoproteomics

KW - Drug Discovery

KW - Isoxazole

KW - Photo-Cross-Linker

KW - Photoaffinity Labeling

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DO - 10.1002/anie.202209947

M3 - RGC 21 - Publication in refereed journal

SN - 1433-7851

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JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 47

M1 - e202209947

ER -

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

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

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GRF: Developing High-Performance Fluorogenic Probes for Detecting Lysine Demethylase Activity

GRF: Developing Isoxazoles as Novel Photo-cross-linkers and Its Application in Chemical Proteomics

Cite this

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

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

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Projects

GRF: Developing High-Performance Fluorogenic Probes for Detecting Lysine Demethylase Activity

GRF: Developing Isoxazoles as Novel Photo-cross-linkers and Its Application in Chemical Proteomics

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