Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening

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

doi:10.3389/fphar.2022.850855

Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening

Front Pharmacol. 2022 Mar 14:13:850855. doi: 10.3389/fphar.2022.850855. eCollection 2022.

Authors

Huizhen Ge¹, Lizeng Peng², Zhou Sun³, Huanxiang Liu⁴, Yulin Shen⁵, Xiaojun Yao¹

Affiliations

¹ College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.
² Institute of Agro-Food Science and Technology Shandong Academy of Agricultural Sciences, Key Laboratory of Agro-Products Processing Technology of Shandong Province, Key Laboratory of Novel Food Resources Processing Ministry of Agriculture, Jinan, China.
³ Academy of Advanced Interdisciplinary Studies, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China.
⁴ School of Pharmacy, Lanzhou University, Lanzhou, China.
⁵ Gansu Computing Center, Lanzhou, China.

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.

Keywords: HPK1 inhibitor; immunotherapy; molecular docking; molecular dynamics simulation; virtual screening.