Jiamei Xu , Yingzhou Li , Xinyi Chen , Junyi Yang , Heye Xia , Wenhai Huang , Shenxin Zeng
{"title":"癌症免疫疗法中靶向 HPK1 的机遇与挑战。","authors":"Jiamei Xu , Yingzhou Li , Xinyi Chen , Junyi Yang , Heye Xia , Wenhai Huang , Shenxin Zeng","doi":"10.1016/j.bioorg.2024.107866","DOIUrl":null,"url":null,"abstract":"<div><div>Hematopoietic Progenitor Kinase 1 (HPK1, also known as MAP4K1) is a hematopoiesis-specific serine/threonine kinase that belongs to the MAP4K family of Ste20-related protein kinases. HPK1 has been identified as a negative regulator of <em>T</em>-cell receptor signaling. Recent studies have indicated that the inhibition or knockout of HPK1 kinase function can effectively alleviate T cell exhaustion, enhance T cell functionality, and improve the therapeutic efficacy of tumor immunotherapy. In recent years, small molecule chemical drugs targeting HPK1 have made significant progress and have become a hot topic in the research and development of tumor immunotherapy drugs. However, the advancement of small molecule drugs that target HPK1 is hindered by various challenges, including the limited selectivity, insufficient immune stimulation, and the ambiguity surrounding role of non-kinase scaffold functions of HPK1 in tumor immune responses. This review briefly describes the biological structure of HPK1 and its related signaling pathways in tumor immunity, systematically discusses the latest research progress in small molecule chemical drugs targeting HPK1. Finally, we summarize and prospect the opportunities and challenges in the drug development of small molecule chemical drugs targeting HPK1 in tumor immunity.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"Article 107866"},"PeriodicalIF":4.5000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Opportunities and challenges for targeting HPK1 in cancer immunotherapy\",\"authors\":\"Jiamei Xu , Yingzhou Li , Xinyi Chen , Junyi Yang , Heye Xia , Wenhai Huang , Shenxin Zeng\",\"doi\":\"10.1016/j.bioorg.2024.107866\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Hematopoietic Progenitor Kinase 1 (HPK1, also known as MAP4K1) is a hematopoiesis-specific serine/threonine kinase that belongs to the MAP4K family of Ste20-related protein kinases. HPK1 has been identified as a negative regulator of <em>T</em>-cell receptor signaling. Recent studies have indicated that the inhibition or knockout of HPK1 kinase function can effectively alleviate T cell exhaustion, enhance T cell functionality, and improve the therapeutic efficacy of tumor immunotherapy. In recent years, small molecule chemical drugs targeting HPK1 have made significant progress and have become a hot topic in the research and development of tumor immunotherapy drugs. However, the advancement of small molecule drugs that target HPK1 is hindered by various challenges, including the limited selectivity, insufficient immune stimulation, and the ambiguity surrounding role of non-kinase scaffold functions of HPK1 in tumor immune responses. This review briefly describes the biological structure of HPK1 and its related signaling pathways in tumor immunity, systematically discusses the latest research progress in small molecule chemical drugs targeting HPK1. Finally, we summarize and prospect the opportunities and challenges in the drug development of small molecule chemical drugs targeting HPK1 in tumor immunity.</div></div>\",\"PeriodicalId\":257,\"journal\":{\"name\":\"Bioorganic Chemistry\",\"volume\":\"153 \",\"pages\":\"Article 107866\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-10-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0045206824007715\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824007715","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Opportunities and challenges for targeting HPK1 in cancer immunotherapy
Hematopoietic Progenitor Kinase 1 (HPK1, also known as MAP4K1) is a hematopoiesis-specific serine/threonine kinase that belongs to the MAP4K family of Ste20-related protein kinases. HPK1 has been identified as a negative regulator of T-cell receptor signaling. Recent studies have indicated that the inhibition or knockout of HPK1 kinase function can effectively alleviate T cell exhaustion, enhance T cell functionality, and improve the therapeutic efficacy of tumor immunotherapy. In recent years, small molecule chemical drugs targeting HPK1 have made significant progress and have become a hot topic in the research and development of tumor immunotherapy drugs. However, the advancement of small molecule drugs that target HPK1 is hindered by various challenges, including the limited selectivity, insufficient immune stimulation, and the ambiguity surrounding role of non-kinase scaffold functions of HPK1 in tumor immune responses. This review briefly describes the biological structure of HPK1 and its related signaling pathways in tumor immunity, systematically discusses the latest research progress in small molecule chemical drugs targeting HPK1. Finally, we summarize and prospect the opportunities and challenges in the drug development of small molecule chemical drugs targeting HPK1 in tumor immunity.
期刊介绍：
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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