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Development of Nitroso-Based Probes for Labeling and Regulation of RAS Proteins in Cancer Cells via Sequential Ene-Ligation and Oxime Condensation.
Li, Yuanyuan; Zhou, Hongling; Liu, Huili; Gan, Youfang; Zheng, Yaying; Sheng, Jia; Wang, Rui.
Afiliación
  • Li Y; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
  • Zhou H; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
  • Liu H; Department of Chemistry, Fudan University, Shanghai 200433, China.
  • Gan Y; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
  • Zheng Y; Department of Chemistry, and The RNA Institute, University at Albany, State University of New York, Albany, New York 12222, United States.
  • Sheng J; Department of Chemistry, and The RNA Institute, University at Albany, State University of New York, Albany, New York 12222, United States.
  • Wang R; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
J Org Chem ; 88(3): 1762-1771, 2023 02 03.
Article en En | MEDLINE | ID: mdl-36691112
Prenyl functionalities have been widely discovered in natural products, nucleic acids, and proteins with significant biological roles in both healthy and diseased cells. In this work, we develop a series of new nitroso-based probes for the labeling, enrichment, and regulation of prenylated RAS protein, which is highly associated with ∼20% of human cancers and used to be regarded as an "undruggable" target via a sequential ene-ligation and oxime condensation (SELOC) process. We found that these nitroso species can rapidly react with prenyl-containing molecules through ene-ligation and install a molecular tag for functional applications under physiological conditions. We first investigated this ligation process on two peptide models and demonstrated its labeling efficiency on various proteins such as myoglobin, lysozyme, RNase A, BSA, and HSP40. We further coupled this reactive platform with proteolysis-targeting chimera technology targeting to increase its efficiency and accuracy, as well as to expand its application range. Using the prenylated RAS protein as the model, we demonstrated that RAS could be efficiently decorated with our nitroso probes, which further condensate with oxime and rapidly react with a pomalidomide-containing hydroxylamine probe for protein degradation. As a result, the RAS protein in both HeLa and A549 cell lines has been determined to be efficiently degraded both in vitro and in vivo. This is the first case targeting post-translational modification other than ligand-protein interaction to degrade and regulate RAS proteins. We envision that our SELOC strategy will have great potential in studying the fundamental structures and functions of prenylated biomolecules and developing new drugs based on these unique cellular pathways.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oximas / Neoplasias Límite: Humans Idioma: En Revista: J Org Chem Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oximas / Neoplasias Límite: Humans Idioma: En Revista: J Org Chem Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos