Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening

Huizhen Ge, Lizeng Peng, Zhou Sun, Huanxiang Liu, Yulin Shen, Xiaojun Yao

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

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 IC50 values below 20 μM, and the most potent one (compound M074-2865) had an IC50 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.

Original languageEnglish
Article number850855
JournalFrontiers in Pharmacology
Volume13
DOIs
Publication statusPublished - 14 Mar 2022
Externally publishedYes

Keywords

  • HPK1 inhibitor
  • immunotherapy
  • molecular docking
  • molecular dynamics simulation
  • virtual screening

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