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Chinese Chemical Letters 2024年第1期35卷 295-299页

作者： Ruiquan Liu Wenwen Duan Wenzhong Yan Jinfeng Zhang Jianjun Cheng iHuman Institute ShanghaiTech UniversityShanghai 201210China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China

The A_(2A)adenosine receptor(A_(2A)AR)has attracted attention as an emerging immunotherapeutic target with several antagonists being evaluated in clinical ***,A_(2A)AR antagonists show limited efficacy as ***,we communicate our design and synthesis of a novel series of A_(2A)AR/histone deacetylase(HDAC)bifunctional inhibitors,based on the core structure of the A_(2A)AR antagonist The new compounds were designed using a pharmacophore-merging strategy and features a tri-substituted pyrimidine *** binding affinity for A_(2A)AR and inhibitory activity against HDACs of all the new compounds were tested.A number of compounds exhibited nanomolar or subnanomolar activity against both targets and some showed equally potent antiproliferative activity against MC38,CT26 and HCT116 colon cancer lines compared to HDAC inhibitors SAHA and MGCD-0103 in *** binding poses of compound 5a in both A_(2A)AR and HDAC1 were predicted by molecular docking ***,these results suggest these tri-substituted pyrimidine derivatives are promising leads for developing A_(2A)AR/HDAC dual-acting compounds as novel antitumor agents.

关键词： Bifunctional A_(2A)AR antagonism HDAC inhibition Cancer Immunotherapy

Genetic Approaches for Neural Circuits Dissection in Non-human Primates

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Neuroscience Bulletin 2023年第10期39卷 1561-1576页

作者： Ling Li Zhen Liu Institute of Neuroscience CAS Center for Excellence in Brain Science and Intelligence TechnologyCAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceChinese Academy of SciencesShanghai 200031China Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology Shanghai 200031China University of Chinese Academy of Sciences Beijing 100049China

Genetic tools,which can be used for the morphology study of specific neurons,pathway-selective connectome mapping,neuronal activity monitoring,and manipulation with a spatiotemporal resolution,have been widely applied to the understanding of complex neural circuit formation,interactions,and functions in ***,similar genetic approaches have been tried in non-human primates(NHPs)in neuroscience studies for dissecting the neural circuits involved in sophisticated behaviors and clinical brain disorders,although they are still very *** this review,we introduce the progress made in the development and application of genetic tools for brain studies on *** also discuss the advantages and limitations of each approach and provide a perspective for using genetic tools to study the neural circuits of NHPs.

关键词： Genetic tool Neural circuit Non-human primate

Structure-based drug discovery of novel fusedpyrazolone carboxamide derivatives as potent and selective AXL inhibitors

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4918-4933页

作者： Feifei Fang Yang Dai Hao Wang Yinchun Ji Xuewu Liang Xia Peng Jiyuan Li Yangrong Zhao Chunpu Li Danyi Wangh Yazhou Li Dong Zhang Dan Zhang Meiyu Geng Hong Liu Jing Ai Yu Zhou lingang laboratory Shanghai 200031China State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Drug Discovery&Development Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Shandong laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China

a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent *** this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability ***,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL *** turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar *** importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL *** together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

关键词： Potential AXL inhibitor Antitumor activity Structure-based drug design Fused-pyrazolone carboxamide

Targeted protein degradation bypassing cereblon and von Hippel-Lindau

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The Innovation 2023年第3期4卷 42-43页

作者： Wenchao Lu lingang laboratory Shanghai 200031China Department of Chemical and Systems Biology Chem-H and Stanford Cancer InstituteStanford School of MedicineStanford UniversityStanfordCA 94305USA

Targeted protein degradation(TPD)has emerged as a new drug discovery approach to wipe out disease-causing proteins by harnessing the ubiquitin-proteasome system(UPS).A major class of molecules in the field are called proteolysis-targeting chimeras(PROTACs),which are heterobifunctional molecules encompassing two ligands that bind to a protein of interest and the E3 ligase,respectively joint by a linker.1 Due to its catalytic mechanism that enables event-driven pharmacology,PROTACs technology can induce an efficient degradation and therefore achieve the pharmacology at a lower dose compared with traditional small molecule inhibitors that exert their inhibition through an occupancy-driven *** the first PROTAC was reported as a proof-ofconcept 20 years ago,this technology has led to a paradigm shift that culminated in the clinic trials of new modalities such as ARV-110,ARV-471,etc.

关键词： mechanism proof enable

Unraveling the complex roles of macrophages in obese adipose tissue:an overview

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Frontiers of Medicine 2024年第2期18卷 205-236页

作者： Chang Peng Jun Chen Rui Wu Haowen Jiang Jia Li Hangzhou Institute for Advanced Study University of Chinese Academy of SciencesHangzhou310000China State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China University of Chinese Academy of Sciences Beijing100049China Department of Prosthodontics Shanghai Engineering Research Center of Advanced Dental Technology and MaterialsShanghai Key Laboratory of Stomatology&Shanghai Research Institute of StomatologyNational Clinical Research Center for Oral DiseasesShanghai Ninth People’s HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghai200011China

Macrophages,a heterogeneous population of innate immune cells,exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic *** activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects,inducing insulin resistance through increased inflammation,impaired thermogenesis,and adipose tissue ***,adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis,facilitating the clearance of dead adipocytes,and promoting mitochondrial *** the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic ***,the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell *** this review,we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity,as well as explore the potential of drug delivery systems targeting macrophages,aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.

关键词： obesity inflammation adipose tissue macrophages adipose tissue homeostasis

Rapid Access to Polysubstituted Tetrahydrocarbazol-4-ones via Sequential Selective C—H Functionalization from N-Nitrosoanilines

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Chinese Journal of Chemistry 2023年第16期41卷 1957-1962页

作者： Chan Li Yanchen Yang Feifei Fang Chaoyi Liu Chunpu Li Dechuan Wang Hong Liu School of Science China Pharmaceutical UniversityNanjingJiangsu 211198China State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of Sciences555 Zu Chong Zhi Road Shanghai 201203 China School of PharmacyChina Pharmaceutical UniversityNanjingJiangsu 211198China lingang laboratory Shanghai 200031China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhouZhejiang 310024China University of Chinese Academy of Sciences Beijing 100049China

Comprehensive Summary Herein,we have developed a strategy of Rh(III)-catalyzed C—H activation of N-nitrosoanilines and iodonium ylides to construct novel tetralydrocarbzol-4-one scaffolds,which provided valuable templates for sequential C—H functionalization such as alkylation,alkenylation,amidation and(hetero)arylation at C^(5)-position of tetralydrocarbzol-4-one with different coupling ***-scale synthesis and further transformations of tetralydrocarbzol-4-one derivatives to Ondansetron and its analogues demonstrated the utility of this protocol,which enabled the concise and diverse construction of biologically active molecules.

关键词： C-H activation Cross dehydrogenative coupling Rhodium catalysis Iridium catalysis Alkenylation Amaidiation Heteroarylation

Recent advances in microsystem approaches for mechanical characterization of soft biological tissues

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Microsystems & Nanoengineering 2022年第4期8卷 1-16页

作者： Enming Song Ya Huang Ningge Huang Yongfeng Mei Xinge Yu John A.Rogers Shanghai Frontiers Science Research Base of Intelligent Optoelectronics and Perception Institute of OptoelectronicsFudan UniversityShanghai 200433China International Institute of Intelligent Nanorobots and Nanosystems Fudan UniversityShanghai 200433China Department of Biomedical Engineering City University of Hong KongHong Kong 999077China Department of Materials Science Fudan UniversityShanghai 200433China Querrey Simpson Institute for Bioelectronics Department of Materials Science and EngineeringDepartments of Biomedical EngineeringNeurological SurgeryChemistryMechanical EngineeringElectrical Engineering and Computer ScienceNorthwestern UniversityEvanstonIL 60208USA

Microsystem technologies for evaluating the mechanical properties of soft biological tissues offer various capabilities relevant to medical research and clinical diagnosis of pathophysiologic *** progress includes(1)the development of tissue-compliant designs that provide minimally invasive interfaces to soft,dynamic biological surfaces and(2)improvements in options for assessments of elastic moduli at spatial scales from cellular resolution to macroscopic areas and across depths from superficial levels to deep *** review summarizes a collection of these technologies,with an emphasis on operational principles,fabrication methods,device designs,integration schemes,and measurement *** core content begins with a discussion of platforms ranging from penetrating filamentary probes and shape-conformal sheets to stretchable arrays of ultrasonic *** sections examine different techniques based on planar microelectromechanical system(MEMS)approaches for biocompatible interfaces to targets that span scales from individual cells to *** highlighted example includes miniature electromechanical devices that allow depth profiling of soft tissue biomechanics across a wide range of *** clinical utility of these technologies is in monitoring changes in tissue properties and in targeting/identifying diseased tissues with distinct variations in *** results suggest future opportunities in engineered systems for biomechanical sensing,spanning a broad scope of applications with relevance to many aspects of health care and biology research.

关键词： advances identifying utility

Dual stimuli-activatable versatile nanoplatform for photodynamic therapy and chemotherapy of triple-negative breast cancer

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Chinese Chemical Letters 2023年第12期34卷 424-432页

作者： Jie Xu Yi Lai Fengyang Wang Zhifeng Zou Renjun Pei Haijun Yu Zhiai Xu School of Chemistry and Molecular Engineering East China Normal UniversityShanghai 200241China State Key laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Key laboratory for Nano-Bio Interface Division of Nanobiomedicine Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences Suzhou 215123China

Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal ***,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to their"always-on"photoactivity in blood *** address this concern,we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast *** set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin(TCPP)with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species(RoS)*** resultant TCPP derivatives are grafted with a poly(ethylene glycol)(PEG)chain via a matrix metalloproteinase-2(MMP-2)-liable peptide spacer and chelated with Mn^(2+)for magnetic resonance imaging(MRI)*** PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific *** further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin(DOX)and perform fluorescence image-guided combinatorial PDT and chemotherapy,which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse *** acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.

关键词： Cancer theranostics Precise therapy Combinatorial therapy Photodynamic therapy Triple-negative breast cancer

Inner nuclear membrane protein TMEM201 maintains endothelial cell migration and angiogenesis by interacting with the LINC complex

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Journal of Molecular Cell Biology 2022年第3期14卷 48-60页

作者： Yutian Zhang Ya Kong Haoran Guo Yun Liu Yi Zang Jia Li University of Chinese Academy of Sciences Beĳing 100049China State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China State Key laboratory of Natural Medicines Jiangsu Key Laboratory of Drug ScreeningChina Pharmaceutical UniversityNanjing 210009China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Open Studio for Druggability Research of Marine Natural Products Pilot National Laboratory for Marine Science and Technology(Qingdao)Qingdao 266237China

The nuclear envelope comprises the outer nuclear membrane,inner nuclear membrane(INM),and ***∼60 INM proteins have been identified,only a few of them have been well characterized,revealing their crucial *** group focused on the INM protein transmembrane protein 201(TMEM201),whose role in cellular function remains to be *** this study,we investigated the role of TMEM201 in endothelial cell migration and *** of TMEM201 expression by short hairpin RNA-mediated interference impeded human umbilical vein endothelial cell(HUVEC)angiogenic behavior in tube formation and fibrin gel bead sprouting ***,TMEM201-deficient HUVECs exhibited impaired migration *** next explored the underlying mechanism and found that the N-terminal of TMEM201 interacted with the linker of nucleoskeleton and cytoskeleton complex and was required for regulating endothelial cell migration and *** in vitro findings were further confirmed by using in vivo *** Tmem201-knockout mice,retinal vessel development was arrested and aortic ring sprouting was *** addition,loss of tmem201 impaired zebrafish intersegmental vessel *** summary,TMEM201 was shown to regulate endothelial cell migration and control the process of *** study is the first to reveal the role of INM proteins in the vascular system and angiogenesis.

关键词： transmembrane protein 201 inner nuclear membrane LINC complex endothelial cell migration angiogenesis

Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders

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Science China(Life Sciences) 2024年第6期67卷 1170-1182页

作者： Jiaming Liu Liangkui Li Dijin Xu Yuqi Li Tao Chen Yeyang Liu Yuqian Bao Yan Wang Longyan Yang Peng Li Li Xu State Key laboratory of Membrane Biology and Tsinghua-Peking Center for Life Sciences Beijing Advanced Innovation Center for Structural BiologySchool of Life SciencesTsinghua UniversityBeijing 100084China Shanghai Qi Zhi Institute Shanghai 200232China Shanghai Key laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Tianjian laboratory of Advanced Biomedical Sciences Zhengzhou UniversityZhengzhou 450001China Department of Physiology School of Basic Medical SciencesGannan Medical UniversityGanzhou 341000China Department of Endocrinology and Metabolism Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s HospitalShanghai 200025China Center for Endocrine Metabolism and Immune Diseases Beijing Luhe HospitalCapital Medical UniversityBeijing 101149China Beijing Key laboratory of Diabetes Research and Care Beijing 101149China

Metabolically healthy obesity refers to obese individuals who do not develop metabolic *** people store fat in subcutaneous adipose tissue(SAT)rather than in visceral adipose tissue(VAT).However,the molecules participating in this specific scenario remain ***18,a lipid droplet(LD)-associated protein,mediates the contact between the endoplasmic reticulum(ER)and LDs to facilitate LD growth and *** the present study,we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and ***18 adipocyte-specific knockout(Rab18 AKO)mice had a decreased volume ratio of SAT to VAT compared with wildtype *** subjected to high-fat diet(HFD),Rab18 AKO mice had increased ER stress and inflammation,reduced adiponectin,and decreased triacylglycerol(TAG)accumulation in *** contrast,TAG accumulation in VAT,brown adipose tissue(BAT)or liver of Rab18AKO mice had a moderate increase without ER stress ***18 AKO mice developed insulin resistance and systematic ***18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT,similar to the counterpart ***,Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress,indicating the involvement of Rab18 in alleviating lipid ***18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired *** conclusion,our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.

关键词： Rab18 subcutaneous adipose tissue(SAT) metabolically healthy obesity(MHO) lipotoxicity ER stress ectopic lipid storage LD-ER contact