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...

Descripción completa

Detalles Bibliográficos
Autores principales: Duong, Men Thi Hoai, Ahn, Hee-Chul
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