Xinmiao Tian , Xianghui Wang , Sichong Chen , Xuefei Sun , Dongxue Shao , Kuo Zhang , Qinghua Gao , Liying Hao
{"title":"Ca2+/钙调素依赖性蛋白激酶II (CaMKII)靶向药物发现:挑战和策略。","authors":"Xinmiao Tian , Xianghui Wang , Sichong Chen , Xuefei Sun , Dongxue Shao , Kuo Zhang , Qinghua Gao , Liying Hao","doi":"10.1016/j.arr.2025.102886","DOIUrl":null,"url":null,"abstract":"<div><div>Calcium (Ca<sup>2+</sup>)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is an emerging drug target for age-related diseases. It is a multifunctional kinase with complex activation modes, numerous isoforms, broad tissue distribution, and a dual role in health and disease. In particular, its isoforms share a high degree of conservation within the catalytic and regulatory domains, with only minor differences confined to the linker region. These characteristics of CaMKII make the development of selectively targeted inhibitors particularly challenging. Current CaMKII inhibitors can be classified into the following categories: CaM-binding site blockers (KN62, KN93); ATP-competitive inhibitors (AS105, GS-680, RA306, RA608, SMP-114, NP202, hesperadin); substrate-binding site blockers (AIP, AC3-I, CN21); and pathway-targeted novel modulators (e.g., Athycaltide-1). However, no CaMKII inhibitor has yet reached clinical approval. Nevertheless, CaMKII remains a compelling target due to its pivotal role in age-related pathologies. Several innovative approaches hold promise for overcoming current limitations, including: activating endogenous degradation of CaMKII by proteolysis-targeting chimeras (PROTACs), applying novel materials such as peptide- or nucleic acid-based agents and CRISPR-Cas9-mediated gene editing approaches, employing tissue-specific delivery systems and engineered drug molecules, and targeting disease-specific signaling pathways. Together, these strategies may pave the way for more precise and effective CaMKII-targeted interventions in aging-associated diseases.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102886"},"PeriodicalIF":12.4000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ca2+/Calmodulin-dependent protein kinase II (CaMKII)-targeted drug discovery: Challenges and strategies\",\"authors\":\"Xinmiao Tian , Xianghui Wang , Sichong Chen , Xuefei Sun , Dongxue Shao , Kuo Zhang , Qinghua Gao , Liying Hao\",\"doi\":\"10.1016/j.arr.2025.102886\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Calcium (Ca<sup>2+</sup>)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is an emerging drug target for age-related diseases. It is a multifunctional kinase with complex activation modes, numerous isoforms, broad tissue distribution, and a dual role in health and disease. In particular, its isoforms share a high degree of conservation within the catalytic and regulatory domains, with only minor differences confined to the linker region. These characteristics of CaMKII make the development of selectively targeted inhibitors particularly challenging. Current CaMKII inhibitors can be classified into the following categories: CaM-binding site blockers (KN62, KN93); ATP-competitive inhibitors (AS105, GS-680, RA306, RA608, SMP-114, NP202, hesperadin); substrate-binding site blockers (AIP, AC3-I, CN21); and pathway-targeted novel modulators (e.g., Athycaltide-1). However, no CaMKII inhibitor has yet reached clinical approval. Nevertheless, CaMKII remains a compelling target due to its pivotal role in age-related pathologies. Several innovative approaches hold promise for overcoming current limitations, including: activating endogenous degradation of CaMKII by proteolysis-targeting chimeras (PROTACs), applying novel materials such as peptide- or nucleic acid-based agents and CRISPR-Cas9-mediated gene editing approaches, employing tissue-specific delivery systems and engineered drug molecules, and targeting disease-specific signaling pathways. Together, these strategies may pave the way for more precise and effective CaMKII-targeted interventions in aging-associated diseases.</div></div>\",\"PeriodicalId\":55545,\"journal\":{\"name\":\"Ageing Research Reviews\",\"volume\":\"112 \",\"pages\":\"Article 102886\"},\"PeriodicalIF\":12.4000,\"publicationDate\":\"2025-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Ageing Research Reviews\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1568163725002326\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ageing Research Reviews","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1568163725002326","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Ca2+/Calmodulin-dependent protein kinase II (CaMKII)-targeted drug discovery: Challenges and strategies
Calcium (Ca2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is an emerging drug target for age-related diseases. It is a multifunctional kinase with complex activation modes, numerous isoforms, broad tissue distribution, and a dual role in health and disease. In particular, its isoforms share a high degree of conservation within the catalytic and regulatory domains, with only minor differences confined to the linker region. These characteristics of CaMKII make the development of selectively targeted inhibitors particularly challenging. Current CaMKII inhibitors can be classified into the following categories: CaM-binding site blockers (KN62, KN93); ATP-competitive inhibitors (AS105, GS-680, RA306, RA608, SMP-114, NP202, hesperadin); substrate-binding site blockers (AIP, AC3-I, CN21); and pathway-targeted novel modulators (e.g., Athycaltide-1). However, no CaMKII inhibitor has yet reached clinical approval. Nevertheless, CaMKII remains a compelling target due to its pivotal role in age-related pathologies. Several innovative approaches hold promise for overcoming current limitations, including: activating endogenous degradation of CaMKII by proteolysis-targeting chimeras (PROTACs), applying novel materials such as peptide- or nucleic acid-based agents and CRISPR-Cas9-mediated gene editing approaches, employing tissue-specific delivery systems and engineered drug molecules, and targeting disease-specific signaling pathways. Together, these strategies may pave the way for more precise and effective CaMKII-targeted interventions in aging-associated diseases.
期刊介绍:
With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends.
ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research.
The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.