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Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening

Hematopoietic progenitor kinase (HPK1) is a negative regulator of T-cell receptor and B-cell signaling, which has been recognized as a novel antitumor target for immunotherapy. In this work, Glide docking-based virtual screening and kinase inhibition assay were performed to identify novel HPK1 inhib...

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Autores principales: Ge, Huizhen, Peng, Lizeng, Sun, Zhou, Liu, Huanxiang, Shen, Yulin, Yao, Xiaojun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967249/
https://www.ncbi.nlm.nih.gov/pubmed/35370676
http://dx.doi.org/10.3389/fphar.2022.850855
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author Ge, Huizhen
Peng, Lizeng
Sun, Zhou
Liu, Huanxiang
Shen, Yulin
Yao, Xiaojun
author_facet Ge, Huizhen
Peng, Lizeng
Sun, Zhou
Liu, Huanxiang
Shen, Yulin
Yao, Xiaojun
author_sort Ge, Huizhen
collection PubMed
description Hematopoietic progenitor kinase (HPK1) is a negative regulator of T-cell receptor and B-cell signaling, which has been recognized as a novel antitumor target for immunotherapy. In this work, Glide docking-based virtual screening and kinase inhibition assay were performed to identify novel HPK1 inhibitors. The kinase inhibition assay results demonstrated five compounds with IC(50) values below 20 μM, and the most potent one (compound M074-2865) had an IC(50) value of 2.93 ± 0.09 μM. Molecular dynamics (MD) simulations were performed to delve into the interaction of sunitinib and the identified compound M074-2865 with the kinase domain of HPK1. The five compounds identified in this work could be considered promising hit compounds for further development of HPK1 inhibitors for immunotherapy.
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spelling pubmed-89672492022-03-31 Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening Ge, Huizhen Peng, Lizeng Sun, Zhou Liu, Huanxiang Shen, Yulin Yao, Xiaojun Front Pharmacol Pharmacology Hematopoietic progenitor kinase (HPK1) is a negative regulator of T-cell receptor and B-cell signaling, which has been recognized as a novel antitumor target for immunotherapy. In this work, Glide docking-based virtual screening and kinase inhibition assay were performed to identify novel HPK1 inhibitors. The kinase inhibition assay results demonstrated five compounds with IC(50) values below 20 μM, and the most potent one (compound M074-2865) had an IC(50) value of 2.93 ± 0.09 μM. Molecular dynamics (MD) simulations were performed to delve into the interaction of sunitinib and the identified compound M074-2865 with the kinase domain of HPK1. The five compounds identified in this work could be considered promising hit compounds for further development of HPK1 inhibitors for immunotherapy. Frontiers Media S.A. 2022-03-14 /pmc/articles/PMC8967249/ /pubmed/35370676 http://dx.doi.org/10.3389/fphar.2022.850855 Text en Copyright © 2022 Ge, Peng, Sun, Liu, Shen and Yao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Ge, Huizhen
Peng, Lizeng
Sun, Zhou
Liu, Huanxiang
Shen, Yulin
Yao, Xiaojun
Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening
title Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening
title_full Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening
title_fullStr Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening
title_full_unstemmed Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening
title_short Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening
title_sort discovery of novel hpk1 inhibitors through structure-based virtual screening
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967249/
https://www.ncbi.nlm.nih.gov/pubmed/35370676
http://dx.doi.org/10.3389/fphar.2022.850855
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