Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR Inhibitor
Abstract Fibroblast growth factor receptor (FGFR) inhibitors are emerged as an important class of targeted therapies in oncology, targeting key pathways associated with tumor growth, angiogenesis, and resistance to conventional treatments. FIIN‐2, the first irreversible covalent pan‐FGFR inhibitor,...
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| Format: | Article |
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412578 |
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| author | Ying Fu Dandan Zhu Xiaojuan Chen Lingzhi Qu Ming Guo Shuhong Zhang Guangyu Xu Zhuchu Chen Maoyu Li Yongheng Chen |
| author_facet | Ying Fu Dandan Zhu Xiaojuan Chen Lingzhi Qu Ming Guo Shuhong Zhang Guangyu Xu Zhuchu Chen Maoyu Li Yongheng Chen |
| author_sort | Ying Fu |
| collection | DOAJ |
| description | Abstract Fibroblast growth factor receptor (FGFR) inhibitors are emerged as an important class of targeted therapies in oncology, targeting key pathways associated with tumor growth, angiogenesis, and resistance to conventional treatments. FIIN‐2, the first irreversible covalent pan‐FGFR inhibitor, has shown promise in overcoming resistance due to gatekeeper mutations; however, its selectivity and molecular mechanisms in tumors remain poorly understood. In this study, an FIIN‐2 chemical probe is designed and synthesized to identify both established and novel targets in hepatocellular carcinoma (HCC) via chemoproteomic profiling. An integrative multi‐omics approach, including chemoproteomic, phosphoproteomic, transcriptomic, and proteomic analyses, is utilized to elucidate the full spectrum of target proteins, signaling pathways, and downstream effectors regulated by FIIN‐2 in HCC. Notably, adenosine monophosphate‐activated protein kinase α1 (AMPKα1) is identified as a novel target of FIIN‐2, with Cys185 identified as its covalent binding site. These findings reveal that FIIN‐2 can induce autophagy by directly binding to and activating AMPKα1, influencing its anti‐tumor activity in HCC cells. Overall, this study greatly advances the understanding of FIIN‐2′s on‐ and off‐target effects, offering a comprehensive view of its molecular mechanisms in cancer cells. The integrative multi‐omics approach provides a valuable framework for the development and optimization of covalent kinase inhibitors. |
| format | Article |
| id | doaj-art-21c3c31e47f44697a3db7ac23bf6bcf4 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-21c3c31e47f44697a3db7ac23bf6bcf42025-08-20T03:06:24ZengWileyAdvanced Science2198-38442025-04-011214n/an/a10.1002/advs.202412578Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR InhibitorYing Fu0Dandan Zhu1Xiaojuan Chen2Lingzhi Qu3Ming Guo4Shuhong Zhang5Guangyu Xu6Zhuchu Chen7Maoyu Li8Yongheng Chen9Department of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaKey Laboratory of Chemical Biology and Traditional Chinese Medicine Ministry of Educational of China Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province College of Chemistry and Chemical Engineering Hunan Normal University Changsha Hunan 410081 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Oncology NHC Key Laboratory of Cancer Proteomics and State Local Joint Engineering Laboratory for Anticancer Drugs National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan 410008 ChinaAbstract Fibroblast growth factor receptor (FGFR) inhibitors are emerged as an important class of targeted therapies in oncology, targeting key pathways associated with tumor growth, angiogenesis, and resistance to conventional treatments. FIIN‐2, the first irreversible covalent pan‐FGFR inhibitor, has shown promise in overcoming resistance due to gatekeeper mutations; however, its selectivity and molecular mechanisms in tumors remain poorly understood. In this study, an FIIN‐2 chemical probe is designed and synthesized to identify both established and novel targets in hepatocellular carcinoma (HCC) via chemoproteomic profiling. An integrative multi‐omics approach, including chemoproteomic, phosphoproteomic, transcriptomic, and proteomic analyses, is utilized to elucidate the full spectrum of target proteins, signaling pathways, and downstream effectors regulated by FIIN‐2 in HCC. Notably, adenosine monophosphate‐activated protein kinase α1 (AMPKα1) is identified as a novel target of FIIN‐2, with Cys185 identified as its covalent binding site. These findings reveal that FIIN‐2 can induce autophagy by directly binding to and activating AMPKα1, influencing its anti‐tumor activity in HCC cells. Overall, this study greatly advances the understanding of FIIN‐2′s on‐ and off‐target effects, offering a comprehensive view of its molecular mechanisms in cancer cells. The integrative multi‐omics approach provides a valuable framework for the development and optimization of covalent kinase inhibitors.https://doi.org/10.1002/advs.202412578AMPKα1chemoproteomicsFGFR inhibitorHCCmulti‐omics |
| spellingShingle | Ying Fu Dandan Zhu Xiaojuan Chen Lingzhi Qu Ming Guo Shuhong Zhang Guangyu Xu Zhuchu Chen Maoyu Li Yongheng Chen Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR Inhibitor Advanced Science AMPKα1 chemoproteomics FGFR inhibitor HCC multi‐omics |
| title | Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR Inhibitor |
| title_full | Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR Inhibitor |
| title_fullStr | Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR Inhibitor |
| title_full_unstemmed | Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR Inhibitor |
| title_short | Integrative Multi‐Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN‐2, a Covalent FGFR Inhibitor |
| title_sort | integrative multi omics approaches reveal selectivity profiles and molecular mechanisms of fiin 2 a covalent fgfr inhibitor |
| topic | AMPKα1 chemoproteomics FGFR inhibitor HCC multi‐omics |
| url | https://doi.org/10.1002/advs.202412578 |
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