The development of small-molecule inhibitors targeting HPK1

Lixin Zhou; Tianyu Wang; Kuojun Zhang; Xiangyu Zhang; Sheng Jiang

doi:10.1016/j.ejmech.2022.114819

The development of small-molecule inhibitors targeting HPK1

Eur J Med Chem. 2022 Dec 15:244:114819. doi: 10.1016/j.ejmech.2022.114819. Epub 2022 Oct 4.

Authors

Lixin Zhou¹, Tianyu Wang², Kuojun Zhang², Xiangyu Zhang³, Sheng Jiang⁴

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy and School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: b19940825@163.com.
² Department of Medicinal Chemistry, School of Pharmacy and School of Engineering, China Pharmaceutical University, Nanjing, 210009, China.
³ Department of Medicinal Chemistry, School of Pharmacy and School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xiangyu.zhang@cpu.edu.cn.
⁴ Department of Medicinal Chemistry, School of Pharmacy and School of Engineering, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: jiang_shengg@126.com.

PMID: 36209628
DOI: 10.1016/j.ejmech.2022.114819

Abstract

Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, is a negative regulator of T cells, B cells, and dendritic cells-mediated immune responses and is primarily expressed in hematopoietic lineage cells. HPK1 regulates different cellular processes by interacting with a variety of substrates and adaptors, including immune cell activation, cellular differentiation, proliferation, adhesion, and apoptosis. In HPK1^KO mice, T cells over-proliferate in response to stimulation by anti-CD3 and anti-CD28 antibodies, and these cells can secrete more proinflammatory cytokines to enhance T-cell activation and tumor growth inhibition when immunized with T cell-dependent antigens. Therefore, HPK1 may be associated with occurrence and development of human malignant tumors and is an effective antitumor immunotherapy target. In this perspective review, the biological rationale and potential of HPK1 as a promising candidate target for cancer immunotherapies and the latest research progress of HPK1 are summarized, with special emphasis on the current small-molecule inhibitors of HPK1 in preclinical and clinical studies.

Keywords: Cancer; Crystal structure; Hematopoietic progenitor kinase 1; Immunotherapy; Inhibitor.

Publication types

Review

MeSH terms

Animals
B-Lymphocytes
Humans
Immunotherapy
Mice
Neoplasms* / drug therapy
Protein Serine-Threonine Kinases*
T-Lymphocytes

Substances

hematopoietic progenitor kinase 1
Protein Serine-Threonine Kinases