Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosph...Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem cells.Yet,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited.In this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in vivo.Remarkably,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 ligase.These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors.Additionally,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.展开更多
Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions.In recent years,molecular glues have been widely used as protein degraders.In addition,however,molecula...Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions.In recent years,molecular glues have been widely used as protein degraders.In addition,however,molecular glues play a variety of vital roles,such as complex stabilization,interactome modulation and transporter inhibition,enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery.Since most molecular glues are identified serendipitously,exploration of their systematic discovery and rational design are important.In this review,representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization,homo-polymerization and hetero-dimerization according to their aggregation modes,and we attempt to elucidate their mechanisms of action.In particular,we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development:starting point,optimization and identification.展开更多
Ubiquitin(Ub)and ubiquitin-like(Ubl)pathways are critical post-translational modifications that determine whether functional proteins are degraded or activated/inactivated.To date,>600 associated enzymes have been ...Ubiquitin(Ub)and ubiquitin-like(Ubl)pathways are critical post-translational modifications that determine whether functional proteins are degraded or activated/inactivated.To date,>600 associated enzymes have been reported that comprise a hierarchical task network(e.g.,E1–E2–E3 cascade enzymatic reaction and deubiquitination)to modulate substrates,including enormous oncoproteins and tumor-suppressive proteins.Several strategies,such as classical biochemical approaches,multiomics,and clinical sample analysis,were combined to elucidate the functional relations between these enzymes and tumors.In this regard,the fundamental advances and follow-on drug discoveries have been crucial in providing vital information concerning contemporary translational efforts to tailor individualized treatment by targeting Ub and Ubl pathways.Correspondingly,emphasizing the current progress of Ub-related pathways as therapeutic targets in cancer is deemed essential.In the present review,we summarize and discuss the functions,clinical significance,and regulatory mechanisms of Ub and Ubl pathways in tumorigenesis as well as the current progress of small-molecular drug discovery.In particular,multiomics analyses were integrated to delineate the complexity of Ub and Ubl modifications for cancer therapy.The present review will provide a focused and up-to-date overview for the researchers to pursue further studies regarding the Ub and Ubl pathways targeted anticancer strategies.展开更多
Cell–cell aggregation is one of the most well-known modes of intercellular communication.The aggregation also plays a vital role in the formation of multicellularity,thus manipulating the growth and development of or...Cell–cell aggregation is one of the most well-known modes of intercellular communication.The aggregation also plays a vital role in the formation of multicellularity,thus manipulating the growth and development of organisms.In the past decades,cell–cell aggregation-related bioprocesses and molecular mechanisms have attracted enormous interest from scientists in biology,and bioengineering.People have developed a series of strategies to artificially regulate cell–cell aggregation through chemical–biological approaches.To date,not only the chemical reagents such as coordination compounds and polymers but also the biomacromolecules such as proteins and nucleic acids,are employed as the“cell glue”to achieve the control of the cell aggregation.So it is meaningful to review the recent advances of the chemical–biological approaches in cell–cell aggregation manipulation.In this review,we discuss the mechanisms and features of recently developed strategies to control cell–cell aggregation.We introduce molecules and designs relying on chemical reactions and biological conjugations respectively,and talk about their advantages and suitable applications.A perspective on the challenges in future applications in cell manipulation and cell-based therapy is also proposed.We expect this review could inspire innovative work on manipulating cell–cell aggregation and further modulate cell–cell interactions in the research of bio/chemical fields.展开更多
The cell cycle is a complex process that involves DNA replication,protein expression,and cell division.Dysregulation of the cell cycle is associated with various diseases.Cyclin-dependent kinases(CDKs)and their corres...The cell cycle is a complex process that involves DNA replication,protein expression,and cell division.Dysregulation of the cell cycle is associated with various diseases.Cyclin-dependent kinases(CDKs)and their corresponding cyclins are major proteins that regulate the cell cycle.In contrast to inhibition,a new approach called proteolysis-targeting chimeras(PROTACs)and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins,achieving targeted degradation.The field of PROTACs and molecular glues has developed rapidly in recent years.In this article,we aim to summarize the latest developments of CDKs and cyclin protein degraders.The selectivity,application,validation and the current state of each CDK degrader will be overviewed.Additionally,possible methods are discussed for the development of degraders for CDK members that still lack them.Overall,this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders,which will be helpful for researchers working on this topic.展开更多
靶向蛋白降解(targeted protein degradation,TPD)技术可通过机体自身的蛋白清理系统(包括泛素蛋白酶体系统和溶酶体降解系统)去除致病靶蛋白,因而比传统的小分子抑制剂拥有更为广阔的应用领域。作为近年来制药行业内正快速发展的一个方...靶向蛋白降解(targeted protein degradation,TPD)技术可通过机体自身的蛋白清理系统(包括泛素蛋白酶体系统和溶酶体降解系统)去除致病靶蛋白,因而比传统的小分子抑制剂拥有更为广阔的应用领域。作为近年来制药行业内正快速发展的一个方向,TPD领域已开发出分子胶水、蛋白水解靶向嵌合体、溶酶体靶向嵌合体系统、自噬靶向嵌合体、自噬连接化合物等技术。目前全球已有30余种TPD药物进入临床试验阶段。该文聚焦于目前研究较为充分或进展较快的5种TPD创新技术,从基本概念、作用原理、技术特点、药物研发进展等角度综述了该领域的研究进展,以期为TPD药物的研发工作提供参考。展开更多
基金the National Natural Science Foundation of China(NSFC,No.82003186,82073691 and 82373134)the International Science and Technology Cooperation Project of China(No.2022YFE0133300)+3 种基金Ningbo Science and Technology Bureau under CM2025 Programme(2020Z092,China)Shenzhen Science and Technology Foundation(JCYJ20210324122006017,China)Tianjin Natural Science Fund(21JCQNJC01910,China)China Postdoctoral Science Foundation e Tianjin Joint Support Program(No.2023T029TJ).
文摘Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem cells.Yet,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited.In this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in vivo.Remarkably,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 ligase.These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors.Additionally,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.
基金supported from the National Natural Science Foundation of China (Nos. 82173672, 82173679, 81903446 and 81973167, China)Natural Science Foundation of Jiangsu Province (BK20190564, China)+1 种基金“Double First-Class” University project of China Pharmaceutical University (CPU2018GY04, China)Free exploration basic research project of Shenzhen Virtual University Park (2021Szvup162, China) for financial support
文摘Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions.In recent years,molecular glues have been widely used as protein degraders.In addition,however,molecular glues play a variety of vital roles,such as complex stabilization,interactome modulation and transporter inhibition,enabling challenging therapeutic targets to be druggable and offering an exciting novel approach for drug discovery.Since most molecular glues are identified serendipitously,exploration of their systematic discovery and rational design are important.In this review,representative examples of molecular glues with various physiological functions are divided into those mediating homo-dimerization,homo-polymerization and hetero-dimerization according to their aggregation modes,and we attempt to elucidate their mechanisms of action.In particular,we aim to highlight some biochemical techniques typically exploited within these representative studies and classify them in terms of three stages of molecular glue development:starting point,optimization and identification.
基金National Natural Science Foundation of China (Grants 81820108022,82003297 and 22177076)Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056,China)+2 种基金Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation (2021KJ03-12,China)The Scientific and Technological Innovation Action Plan of Science and Technology Commission of Shanghai (20JC1411300,China)ChenGuang project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG49,China).
文摘Ubiquitin(Ub)and ubiquitin-like(Ubl)pathways are critical post-translational modifications that determine whether functional proteins are degraded or activated/inactivated.To date,>600 associated enzymes have been reported that comprise a hierarchical task network(e.g.,E1–E2–E3 cascade enzymatic reaction and deubiquitination)to modulate substrates,including enormous oncoproteins and tumor-suppressive proteins.Several strategies,such as classical biochemical approaches,multiomics,and clinical sample analysis,were combined to elucidate the functional relations between these enzymes and tumors.In this regard,the fundamental advances and follow-on drug discoveries have been crucial in providing vital information concerning contemporary translational efforts to tailor individualized treatment by targeting Ub and Ubl pathways.Correspondingly,emphasizing the current progress of Ub-related pathways as therapeutic targets in cancer is deemed essential.In the present review,we summarize and discuss the functions,clinical significance,and regulatory mechanisms of Ub and Ubl pathways in tumorigenesis as well as the current progress of small-molecular drug discovery.In particular,multiomics analyses were integrated to delineate the complexity of Ub and Ubl modifications for cancer therapy.The present review will provide a focused and up-to-date overview for the researchers to pursue further studies regarding the Ub and Ubl pathways targeted anticancer strategies.
基金Nankai University,Grant/Award Number:63211050NationalNatural Science Foundation of China,Grant/Award Numbers:21874075,22074068,591859123。
文摘Cell–cell aggregation is one of the most well-known modes of intercellular communication.The aggregation also plays a vital role in the formation of multicellularity,thus manipulating the growth and development of organisms.In the past decades,cell–cell aggregation-related bioprocesses and molecular mechanisms have attracted enormous interest from scientists in biology,and bioengineering.People have developed a series of strategies to artificially regulate cell–cell aggregation through chemical–biological approaches.To date,not only the chemical reagents such as coordination compounds and polymers but also the biomacromolecules such as proteins and nucleic acids,are employed as the“cell glue”to achieve the control of the cell aggregation.So it is meaningful to review the recent advances of the chemical–biological approaches in cell–cell aggregation manipulation.In this review,we discuss the mechanisms and features of recently developed strategies to control cell–cell aggregation.We introduce molecules and designs relying on chemical reactions and biological conjugations respectively,and talk about their advantages and suitable applications.A perspective on the challenges in future applications in cell manipulation and cell-based therapy is also proposed.We expect this review could inspire innovative work on manipulating cell–cell aggregation and further modulate cell–cell interactions in the research of bio/chemical fields.
基金supported by National Key R&D Program of China (Nos.2021YFA1302100,2020YFE0202200,and 2021YFA1300200)National Natural Science Foundation of China (No.82125034)+1 种基金Fellowship of China Postdoctoral Science Foundation (No.2021M701953)the Foundation of Shuimu Tsinghua Scholar Program (No.2021SM110).
文摘The cell cycle is a complex process that involves DNA replication,protein expression,and cell division.Dysregulation of the cell cycle is associated with various diseases.Cyclin-dependent kinases(CDKs)and their corresponding cyclins are major proteins that regulate the cell cycle.In contrast to inhibition,a new approach called proteolysis-targeting chimeras(PROTACs)and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins,achieving targeted degradation.The field of PROTACs and molecular glues has developed rapidly in recent years.In this article,we aim to summarize the latest developments of CDKs and cyclin protein degraders.The selectivity,application,validation and the current state of each CDK degrader will be overviewed.Additionally,possible methods are discussed for the development of degraders for CDK members that still lack them.Overall,this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders,which will be helpful for researchers working on this topic.
文摘靶向蛋白降解(targeted protein degradation,TPD)技术可通过机体自身的蛋白清理系统(包括泛素蛋白酶体系统和溶酶体降解系统)去除致病靶蛋白,因而比传统的小分子抑制剂拥有更为广阔的应用领域。作为近年来制药行业内正快速发展的一个方向,TPD领域已开发出分子胶水、蛋白水解靶向嵌合体、溶酶体靶向嵌合体系统、自噬靶向嵌合体、自噬连接化合物等技术。目前全球已有30余种TPD药物进入临床试验阶段。该文聚焦于目前研究较为充分或进展较快的5种TPD创新技术,从基本概念、作用原理、技术特点、药物研发进展等角度综述了该领域的研究进展,以期为TPD药物的研发工作提供参考。
