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Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor

Numerous inhibitors of tyrosine-protein kinase KIT, a receptor tyrosine kinase, have been explored as a viable therapy for the treatment of gastrointestinal stromal tumor (GIST). However, drug resistance due to acquired mutations in KIT makes these drugs almost useless. The present study was designe...

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Detalles Bibliográficos
Autores principales: Jiang, Lili, Zhang, Zhongmin, Wang, Zhen, Liu, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: De Gruyter 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020195/
https://www.ncbi.nlm.nih.gov/pubmed/33851030
http://dx.doi.org/10.1515/biol-2021-0036
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author Jiang, Lili
Zhang, Zhongmin
Wang, Zhen
Liu, Yong
author_facet Jiang, Lili
Zhang, Zhongmin
Wang, Zhen
Liu, Yong
author_sort Jiang, Lili
collection PubMed
description Numerous inhibitors of tyrosine-protein kinase KIT, a receptor tyrosine kinase, have been explored as a viable therapy for the treatment of gastrointestinal stromal tumor (GIST). However, drug resistance due to acquired mutations in KIT makes these drugs almost useless. The present study was designed to screen the novel inhibitors against the activity of the KIT mutants through pharmacophore modeling and molecular docking. The best two pharmacophore models were established using the KIT mutants’ crystal complexes and were used to screen the new compounds with possible KIT inhibitory activity against both activation loop and ATP-binding mutants. As a result, two compounds were identified as potential candidates from the virtual screening, which satisfied the potential binding capabilities, molecular modeling characteristics, and predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Further molecular docking simulations showed that two compounds made strong hydrogen bond interaction with different KIT mutant proteins. Our results indicated that pharmacophore models based on the receptor–ligand complex had excellent ability to screen KIT inhibitors, and two compounds may have the potential to develop further as the future KIT inhibitors for GIST treatment.
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spelling pubmed-80201952021-04-12 Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor Jiang, Lili Zhang, Zhongmin Wang, Zhen Liu, Yong Open Life Sci Research Article Numerous inhibitors of tyrosine-protein kinase KIT, a receptor tyrosine kinase, have been explored as a viable therapy for the treatment of gastrointestinal stromal tumor (GIST). However, drug resistance due to acquired mutations in KIT makes these drugs almost useless. The present study was designed to screen the novel inhibitors against the activity of the KIT mutants through pharmacophore modeling and molecular docking. The best two pharmacophore models were established using the KIT mutants’ crystal complexes and were used to screen the new compounds with possible KIT inhibitory activity against both activation loop and ATP-binding mutants. As a result, two compounds were identified as potential candidates from the virtual screening, which satisfied the potential binding capabilities, molecular modeling characteristics, and predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Further molecular docking simulations showed that two compounds made strong hydrogen bond interaction with different KIT mutant proteins. Our results indicated that pharmacophore models based on the receptor–ligand complex had excellent ability to screen KIT inhibitors, and two compounds may have the potential to develop further as the future KIT inhibitors for GIST treatment. De Gruyter 2021-04-03 /pmc/articles/PMC8020195/ /pubmed/33851030 http://dx.doi.org/10.1515/biol-2021-0036 Text en © 2021 Lili Jiang et al., published by De Gruyter http://creativecommons.org/licenses/by/4.0 This work is licensed under the Creative Commons Attribution 4.0 International License.
spellingShingle Research Article
Jiang, Lili
Zhang, Zhongmin
Wang, Zhen
Liu, Yong
Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
title Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
title_full Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
title_fullStr Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
title_full_unstemmed Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
title_short Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
title_sort discovery of novel potential kit inhibitors for the treatment of gastrointestinal stromal tumor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020195/
https://www.ncbi.nlm.nih.gov/pubmed/33851030
http://dx.doi.org/10.1515/biol-2021-0036
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