Cargando…
Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are related to cell proliferation, gene expression, and cell death. JNK isoform 3 (JNK3) is an important therapeutic target in varieties of pathological conditions including cancers and neuronal...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9501523/ https://www.ncbi.nlm.nih.gov/pubmed/36145648 http://dx.doi.org/10.3390/pharmaceutics14091900 |
_version_ | 1784795495925809152 |
---|---|
author | Duong, Men Thi Hoai Ahn, Hee-Chul |
author_facet | Duong, Men Thi Hoai Ahn, Hee-Chul |
author_sort | Duong, Men Thi Hoai |
collection | PubMed |
description | The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are related to cell proliferation, gene expression, and cell death. JNK isoform 3 (JNK3) is an important therapeutic target in varieties of pathological conditions including cancers and neuronal death. There is no approved drug targeting JNKs. To discover chemical inhibitors of JNK3, virtual fragment screening, the saturation transfer difference (STD) NMR, in vitro kinase assay, and X-ray crystallography were employed. A total of 27 fragments from the virtually selected 494 compounds were identified as initial hits via STD NMR and some compounds showed the inhibition of the activity of JNK3 in vitro. The structures of JNK3 with a fragment and a potent inhibitor were determined by X-ray crystallography. The fragment and inhibitor shared a common JNK3-binding feature. The result shows that fragment screening by NMR spectroscopy is a very efficient method to screen JNK3 binders and the structure of JNK3-inhibitor complex can be used to design and develop more potent inhibitors. |
format | Online Article Text |
id | pubmed-9501523 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95015232022-09-24 Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors Duong, Men Thi Hoai Ahn, Hee-Chul Pharmaceutics Article The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are related to cell proliferation, gene expression, and cell death. JNK isoform 3 (JNK3) is an important therapeutic target in varieties of pathological conditions including cancers and neuronal death. There is no approved drug targeting JNKs. To discover chemical inhibitors of JNK3, virtual fragment screening, the saturation transfer difference (STD) NMR, in vitro kinase assay, and X-ray crystallography were employed. A total of 27 fragments from the virtually selected 494 compounds were identified as initial hits via STD NMR and some compounds showed the inhibition of the activity of JNK3 in vitro. The structures of JNK3 with a fragment and a potent inhibitor were determined by X-ray crystallography. The fragment and inhibitor shared a common JNK3-binding feature. The result shows that fragment screening by NMR spectroscopy is a very efficient method to screen JNK3 binders and the structure of JNK3-inhibitor complex can be used to design and develop more potent inhibitors. MDPI 2022-09-08 /pmc/articles/PMC9501523/ /pubmed/36145648 http://dx.doi.org/10.3390/pharmaceutics14091900 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Duong, Men Thi Hoai Ahn, Hee-Chul Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors |
title | Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors |
title_full | Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors |
title_fullStr | Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors |
title_full_unstemmed | Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors |
title_short | Fragment-Based and Structural Investigation for Discovery of JNK3 Inhibitors |
title_sort | fragment-based and structural investigation for discovery of jnk3 inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9501523/ https://www.ncbi.nlm.nih.gov/pubmed/36145648 http://dx.doi.org/10.3390/pharmaceutics14091900 |
work_keys_str_mv | AT duongmenthihoai fragmentbasedandstructuralinvestigationfordiscoveryofjnk3inhibitors AT ahnheechul fragmentbasedandstructuralinvestigationfordiscoveryofjnk3inhibitors |