{"title":"定向降解蛋白质的下一步行动","authors":"Mackenzie W. Krone, Craig M. Crews","doi":"10.1016/j.chembiol.2024.10.004","DOIUrl":null,"url":null,"abstract":"Targeted protein degradation (TPD) has greatly advanced as a therapeutic strategy in the past two decades, and we are on the cusp of rationally designed protein degraders reaching clinical approval. Offering pharmacological advantages relative to occupancy-driven protein inhibition, chemical methods for regulating biomolecular proximity have provided opportunities to tackle disease-related targets that were undruggable. Despite the pre-clinical success of designed degraders and existence of clinical therapies that serendipitously utilize TPD, expansion of the TPD toolbox is necessary to identify and characterize the next generation of molecular degraders. Here we highlight three areas for continued growth in the field that should be prioritized: expansion of TPD platform with greater spatiotemporal precision, increased throughput of degrader synthesis, and optimization of cooperativity in chemically induced protein complexes. The future is bright for TPD in medicine, and we expect that innovative approaches will increase therapeutic applications of proximity-induced pharmacology.","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"84 1","pages":""},"PeriodicalIF":6.6000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Next steps for targeted protein degradation\",\"authors\":\"Mackenzie W. Krone, Craig M. Crews\",\"doi\":\"10.1016/j.chembiol.2024.10.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Targeted protein degradation (TPD) has greatly advanced as a therapeutic strategy in the past two decades, and we are on the cusp of rationally designed protein degraders reaching clinical approval. Offering pharmacological advantages relative to occupancy-driven protein inhibition, chemical methods for regulating biomolecular proximity have provided opportunities to tackle disease-related targets that were undruggable. Despite the pre-clinical success of designed degraders and existence of clinical therapies that serendipitously utilize TPD, expansion of the TPD toolbox is necessary to identify and characterize the next generation of molecular degraders. Here we highlight three areas for continued growth in the field that should be prioritized: expansion of TPD platform with greater spatiotemporal precision, increased throughput of degrader synthesis, and optimization of cooperativity in chemically induced protein complexes. The future is bright for TPD in medicine, and we expect that innovative approaches will increase therapeutic applications of proximity-induced pharmacology.\",\"PeriodicalId\":265,\"journal\":{\"name\":\"Cell Chemical Biology\",\"volume\":\"84 1\",\"pages\":\"\"},\"PeriodicalIF\":6.6000,\"publicationDate\":\"2024-11-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Chemical Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.chembiol.2024.10.004\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Chemical Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.chembiol.2024.10.004","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Targeted protein degradation (TPD) has greatly advanced as a therapeutic strategy in the past two decades, and we are on the cusp of rationally designed protein degraders reaching clinical approval. Offering pharmacological advantages relative to occupancy-driven protein inhibition, chemical methods for regulating biomolecular proximity have provided opportunities to tackle disease-related targets that were undruggable. Despite the pre-clinical success of designed degraders and existence of clinical therapies that serendipitously utilize TPD, expansion of the TPD toolbox is necessary to identify and characterize the next generation of molecular degraders. Here we highlight three areas for continued growth in the field that should be prioritized: expansion of TPD platform with greater spatiotemporal precision, increased throughput of degrader synthesis, and optimization of cooperativity in chemically induced protein complexes. The future is bright for TPD in medicine, and we expect that innovative approaches will increase therapeutic applications of proximity-induced pharmacology.
Cell Chemical BiologyBiochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍:
Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.