Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening

文献类型： 外文期刊

第一作者： Ge, Huizhen

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

作者机构：

关键词： HPK1 inhibitor; immunotherapy; virtual screening; molecular docking; molecular dynamics simulation

期刊名称：FRONTIERS IN PHARMACOLOGY （ 影响因子：5.811； 五年影响因子：6.006 ）

ISSN：

年卷期： 2022 年 13 卷

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收录情况： SCI

摘要： 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 mu M, and the most potent one (compound M074-2865) had an IC50 value of 2.93 +/- 0.09 mu M. 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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