Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails
Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinas...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2068148 |
| _version_ | 1828371603503710208 |
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| author | Seo-Jung Han Jae Eun Jung Do Hee Oh Minsup Kim Jae-Min Kim Kyung-Sook Chung Hee-Soo Han Jeong-Hun Lee Kyung-Tae Lee Hee Jin Jeong In Ho Park Eunkyeong Jeon Jeon-Soo Shin Dongkeun Hwang Art E. Cho Duck-Hyung Lee Taebo Sim |
| author_facet | Seo-Jung Han Jae Eun Jung Do Hee Oh Minsup Kim Jae-Min Kim Kyung-Sook Chung Hee-Soo Han Jeong-Hun Lee Kyung-Tae Lee Hee Jin Jeong In Ho Park Eunkyeong Jeon Jeon-Soo Shin Dongkeun Hwang Art E. Cho Duck-Hyung Lee Taebo Sim |
| author_sort | Seo-Jung Han |
| collection | DOAJ |
| description | Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region. |
| first_indexed | 2024-04-14T06:51:45Z |
| format | Article |
| id | doaj.art-c5691771b8354940857012412b9bca79 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-14T06:51:45Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-c5691771b8354940857012412b9bca792022-12-22T02:07:01ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013711257127710.1080/14756366.2022.2068148Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tailsSeo-Jung Han0Jae Eun Jung1Do Hee Oh2Minsup Kim3Jae-Min Kim4Kyung-Sook Chung5Hee-Soo Han6Jeong-Hun Lee7Kyung-Tae Lee8Hee Jin Jeong9In Ho Park10Eunkyeong Jeon11Jeon-Soo Shin12Dongkeun Hwang13Art E. Cho14Duck-Hyung Lee15Taebo Sim16Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of KoreaChemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of KoreaChemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of KoreaDrug Discovery Institute, inCerebro Co., Ltd., Seoul, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of KoreaChemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of KoreaSeverance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of KoreaInstitute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of KoreaSeverance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of KoreaChemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of KoreaDrug Discovery Institute, inCerebro Co., Ltd., Seoul, Republic of KoreaDepartment of Chemistry, Sogang University, Seoul, Republic of KoreaChemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of KoreaIdentification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region.https://www.tandfonline.com/doi/10.1080/14756366.2022.2068148Type-II kinaseLckDSS-induced colitis |
| spellingShingle | Seo-Jung Han Jae Eun Jung Do Hee Oh Minsup Kim Jae-Min Kim Kyung-Sook Chung Hee-Soo Han Jeong-Hun Lee Kyung-Tae Lee Hee Jin Jeong In Ho Park Eunkyeong Jeon Jeon-Soo Shin Dongkeun Hwang Art E. Cho Duck-Hyung Lee Taebo Sim Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails Journal of Enzyme Inhibition and Medicinal Chemistry Type-II kinase Lck DSS-induced colitis |
| title | Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails |
| title_full | Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails |
| title_fullStr | Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails |
| title_full_unstemmed | Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails |
| title_short | Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails |
| title_sort | identification of highly selective type ii kinase inhibitors with chiral peptidomimetic tails |
| topic | Type-II kinase Lck DSS-induced colitis |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2068148 |
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