Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics
Abstract Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinant...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-03-01
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| Series: | MedComm – Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mog2.69 |
| _version_ | 1797235590799818752 |
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| author | Tian‐Hua Wei Meng‐Yi Lu Si‐Hui Yao Yu‐Qi Hong Jin Yang Meng‐Yuan Zhang Yu‐Qi Yin Yu‐Jie Han Qing‐Qing Li Zi‐Xuan Wang Yi‐Bo Wang Zhen‐Jiang Tong Yun Zhou Wei‐Chen Dai Yan‐Cheng Yu Shan‐Liang Sun Ye Yang Nian‐Guang Li Zhi‐Hao Shi |
| author_facet | Tian‐Hua Wei Meng‐Yi Lu Si‐Hui Yao Yu‐Qi Hong Jin Yang Meng‐Yuan Zhang Yu‐Qi Yin Yu‐Jie Han Qing‐Qing Li Zi‐Xuan Wang Yi‐Bo Wang Zhen‐Jiang Tong Yun Zhou Wei‐Chen Dai Yan‐Cheng Yu Shan‐Liang Sun Ye Yang Nian‐Guang Li Zhi‐Hao Shi |
| author_sort | Tian‐Hua Wei |
| collection | DOAJ |
| description | Abstract Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure‐selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure‐based methods for discovering and designing selective JAKi. Other structure‐based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients. |
| first_indexed | 2024-04-24T16:50:23Z |
| format | Article |
| id | doaj.art-29262a2be1a6426fa1afb92378ccb3fb |
| institution | Directory Open Access Journal |
| issn | 2769-6448 |
| language | English |
| last_indexed | 2024-04-24T16:50:23Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm – Oncology |
| spelling | doaj.art-29262a2be1a6426fa1afb92378ccb3fb2024-03-29T03:56:48ZengWileyMedComm – Oncology2769-64482024-03-0131n/an/a10.1002/mog2.69Insight into Janus kinases specificity: From molecular architecture to cancer therapeuticsTian‐Hua Wei0Meng‐Yi Lu1Si‐Hui Yao2Yu‐Qi Hong3Jin Yang4Meng‐Yuan Zhang5Yu‐Qi Yin6Yu‐Jie Han7Qing‐Qing Li8Zi‐Xuan Wang9Yi‐Bo Wang10Zhen‐Jiang Tong11Yun Zhou12Wei‐Chen Dai13Yan‐Cheng Yu14Shan‐Liang Sun15Ye Yang16Nian‐Guang Li17Zhi‐Hao Shi18National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaDepartment of Biostatistics, School of Public Health Nanjing Medical University Nanjing ChinaEditorial Department of Progress in Pharmaceutical Sciences China Pharmaceutical University Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaSchool of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing ChinaLaboratory of Molecular Design and Drug Discovery, School of Science China Pharmaceutical University Nanjing ChinaAbstract Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure‐selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure‐based methods for discovering and designing selective JAKi. Other structure‐based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients.https://doi.org/10.1002/mog2.69crystal structureinhibitorJAKselectivitystructure‐activity relationship |
| spellingShingle | Tian‐Hua Wei Meng‐Yi Lu Si‐Hui Yao Yu‐Qi Hong Jin Yang Meng‐Yuan Zhang Yu‐Qi Yin Yu‐Jie Han Qing‐Qing Li Zi‐Xuan Wang Yi‐Bo Wang Zhen‐Jiang Tong Yun Zhou Wei‐Chen Dai Yan‐Cheng Yu Shan‐Liang Sun Ye Yang Nian‐Guang Li Zhi‐Hao Shi Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics MedComm – Oncology crystal structure inhibitor JAK selectivity structure‐activity relationship |
| title | Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics |
| title_full | Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics |
| title_fullStr | Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics |
| title_full_unstemmed | Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics |
| title_short | Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics |
| title_sort | insight into janus kinases specificity from molecular architecture to cancer therapeutics |
| topic | crystal structure inhibitor JAK selectivity structure‐activity relationship |
| url | https://doi.org/10.1002/mog2.69 |
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