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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Bibliographic Details
Published in:Frontiers in pharmacology 2022-03, Vol.13, p.850855
Main Authors: Ge, Huizhen, Peng, Lizeng, Sun, Zhou, Liu, Huanxiang, Shen, Yulin, Yao, Xiaojun
Format: Article
Language:English
Subjects:
HPK1 inhibitor
immunotherapy
molecular docking
molecular dynamics simulation
Pharmacology
virtual screening
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Summary: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 values below 20 μM, and the most potent one (compound M074-2865) had an IC 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.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2022.850855