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molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH

Acta Pharmaceutica Sinica B 2024年第9期14卷 4001-4013页

作者： Ziqi Huang Kun Zhang Yurui Jiang Mengmeng Wang Mei Li Yuda Guo Ruolin Gao Ning Li Chenyang Wang Jia Chen Jiefu Wang Ning Liu Xiang Liu Shuangwei Liu Mingming Wei Cheng Yang Guang Yang The State Key Laboratory of Medicinal Chemical Biology College of Life SciencesCollege of PharmacyNankai UniversityTianjin 300071China Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China

Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and ***,targeting CSCs has emerged as a promising avenue for cancer ***,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem ***,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are *** 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 ***,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 *** 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 ***,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.

关键词： molecular glue Targeted protein degradation PHGDH Cancer stem cells PROTACs

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molecular glues modulate protein functions by inducing protein aggregation:A promising therapeutic strategy of small molecules for disease treatment

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3548-3566页

作者： Hongyu Wu Hong Yao Chen He Yilin Jia Zheying Zhu Shengtao Xu Dahong Li Jinyi Xu State Key Laboratory of Natural Medicines Department of Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China Division of molecular Therapeutics&Formulation School of Pharmacythe University of NottinghamUniversity Park CampusNottingham NG72RDUK Key Laboratory of Structure-Based Drug Design&Discovery Ministry of EducationSchool of Traditional Chinese Materia MedicaShenyang Pharmaceutical UniversityShenyang 110016China

molecular glues can specifically induce aggregation between two or more proteins to modulate biological *** recent years,molecular glues have been widely used as protein *** 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 *** most molecular glues are identified serendipitously,exploration of their systematic discovery and rational design are *** 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 *** 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.

关键词： Small molecule molecular glue Dimerization Polymerization Protein–protein interaction

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Function,mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4341-4372页

作者： Yanyu Jiang Shuaishuai Ni Biying Xiao Lijun Jia Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China

Ubiquitin(Ub)and ubiquitin-like(Ubl)pathways are critical post-translational modifications that determine whether functional proteins are degraded or activated/*** 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 *** strategies,such as classical biochemical approaches,multiomics,and clinical sample analysis,were combined to elucidate the functional relations between these enzymes and *** 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 ***,emphasizing the current progress of Ub-related pathways as therapeutic targets in cancer is deemed *** 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 *** particular,multiomics analyses were integrated to delineate the complexity of Ub and Ubl modifications for cancer *** 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.

关键词： Ub and Ubl modifications Ub-activating enzyme Ub-conjugating enzyme Ub ligase Multiomics analyses Drug discovery Small molecule inhibitor molecular glue

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Discovery of small molecule degraders for modulating cell cycle

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Frontiers of Medicine 2023年第5期17卷 823-854页

作者： Liguo Wang Zhouli Yang Guangchen Li Yongbo Liu Chao Ai Yu Rao MOE Key Laboratory of Protein Sciences School of Pharmaceutical SciencesMOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical BiologyTsinghua UniversityBeijing100084China Beijing Tsinghua Changgung Hospital School of Clinical MedicineTsinghua UniversityBeijing102218China

The cell cycle is a complex process that involves DNA replication,protein expression,and cell *** of the cell cycle is associated with various ***-dependent kinases(CDKs)and their corresponding cyclins are major proteins that regulate the cell *** 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 *** field of PROTACs and molecular glues has developed rapidly in recent *** this article,we aim to summarize the latest developments of CDKs and cyclin protein *** selectivity,application,validation and the current state of each CDK degrader will be ***,possible methods are discussed for the development of degraders for CDK members that still lack ***,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.

关键词： PROTAC molecular glue degrader cell cycle CDK cyclin

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Chemical–biological approaches for the direct regulation of cell–cell aggregation

Aggregate

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Aggregate 2022年第2期3卷 33-49页

作者： Jia-Yi Ma Ya-Xin Wang Yan Huang Yi Zhang Yun-Xi Cui De-Ming Kong State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjinP.R.China School of Pharmacy Binzhou Medical UniversityYantaiShandongP.R.China College of Life Sciences Nankai UniversityTianjinP.R.China Tianjin Key Laboratory of Biosensing and molecular Recognition Research Centre for Analytical SciencesCollege of ChemistryNankai UniversityTianjinP.R.China

Cell–cell aggregation is one of the most well-known modes of intercellular *** aggregation also plays a vital role in the formation of multicellularity,thus manipulating the growth and development of *** the past decades,cell–cell aggregation-related bioprocesses and molecular mechanisms have attracted enormous interest from scientists in biology,and *** have developed a series of strategies to artificially regulate cell–cell aggregation through chemical–biological *** 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 *** it is meaningful to review the recent advances of the chemical–biological approaches in cell–cell aggregation *** this review,we discuss the mechanisms and features of recently developed strategies to control cell–cell *** 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 *** 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.

关键词： cell-cell aggregation molecular glue precise regulation

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