Abstract
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.
Keywords:
DSS-induced colitis; Lck; Type-II kinase.
MeSH terms
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Animals
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Mice
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Peptidomimetics* / pharmacology
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Protein Kinase Inhibitors / pharmacology
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src-Family Kinases
Substances
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Peptidomimetics
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Protein Kinase Inhibitors
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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src-Family Kinases
Grants and funding
This work was supported by Korea Institute of Science and Technology (KIST), the National Research Foundation of Korea (NRF) funded by the Korean government (MEST) [2017R1A2B3006704, 2019R1A6A1A03032869, NRF2016M3A9B5940991, NRF-2021R1A2C3011992], the Brain Korea 21 FOUR Project for Medical Science in Yonsei University College of Medicine, and the Technology Development Program to Solve Climate Change of the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (NRF-2020M1A2A2079798). This research was supported by the National Research Council of Science & Technology (NST) granted by the Korea government (MSIT) (No. CPS21061-100).