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A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

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Acta Pharmaceutica Sinica B 2024年第1期14卷 207-222页

作者： Hongrui Zhu Yamin Gao Liyun Liu Mengyu Tao Xiao Lin Yijia Cheng Yaoyao Shen Haitao Xue Li Guan Huimin Zhao Li Liu Shuping Wang Fan Yang Yongjun Zhou Hongze Liao Fan Sun Houwen Lin Research Center for Marine drugs Department of PharmacyRen Ji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of Oncology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China Institute of Marine drugs Guangxi University of Chinese MedicineNanning 530200China state key laboratory of new drug and pharmaceutical process Shanghai Professional and Technical Ser-vice Center for Biological Material Drug-ability EvaluationShanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 200437China Institute of Marine Biomedicine Shenzhen PolytechnicShenzhen 518055China

Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin ***,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin ***,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC ***,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

关键词： Colorectal cancer TNKSeUSP25 interaction Multi-drug resistance TNKS overexpression Wnt pathway Apoptosis Neoantimycin analog

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Pharmacological insights into autophagy modulation in autoimmune diseases

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3364-3378页

作者： Ming-Yue Wu Er-Jin Wang Du Feng Min Li Richard D.Ye Jia-Hong Lu state key laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 9999078China key laboratory of Protein Modification and Degradation State Key Laboratory of Respiratory DiseaseCollege of Basic Medical ScienceGuangzhou Medical UniversityGuangzhou 510000China School of pharmaceutical Sciences National and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510000China Kobilka Institute of Innovative drug Discovery School of Life and Health Sciencesthe Chinese University of Hong KongShenzhen 518000China

As a cellular bulk degradation and survival mechanism,autophagy is implicated in diverse biological ***-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus(SLE)and inflammatory bowel disease(IBD),indicating that autophagy dysregulation may be involved in the development of autoimmune diseases.A series of autophagy modulators have displayed protective effects on autoimmune disease models,highlighting the emerging role of autophagy modulators in treating autoimmune *** review explores the roles of autophagy in the autoimmune diseases,with emphasis on four major autoimmune diseases[SLE,rheumatoid arthritis(RA),IBD,and experimental autoimmune encephalomyelitis(EAE)].More importantly,the therapeutic potentials of small molecular autophagy modulators(including autophagy inducers and inhibitors)on autoimmune diseases are comprehensively analyzed.

关键词： Autophagy Autoimmune disease Systemic lupus erythematosus Inflammatory bowel disease Rheumatoid arthritis Experimental autoimmune encephalomyelitis Autophagy inducer Autophagy inhibitor

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Schisandra lignans ameliorate nonalcoholic steatohepatitis by regulating aberrant metabolism of phosphatidylethanolamines

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3545-3560页

作者： Lijuan Xue Keanqi Liu Caixia Yan Junling Dun Yexin Xu Linlin Wu Huizhu Yang Huafang Liu Lin Xie Guangji Wang Yan Liang key lab of drug Metabolism&Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Zhejiang Provincial key laboratory for drug Evaluation and Clinical Research Department of Clinical Pharmacythe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Analytical Applications Center Shimadzu(China)Co.Ltd.Shanghai 200233China

Nonalcoholic steatohepatitis(NASH)is a spectrum of chronic liver disease characterized by hepatic lipid metabolism *** reports emphasized the contribution of triglyceride and diglyceride accumulation to NASH,while the other lipids associated with the NASH pathogenesis remained *** specific purpose of our study was to explore a novel pathogenesis and treatment strategy of NASH via profiling the metabolic characteristics of ***,multi-omics techniques based on LC—Q-TOF/MS,LC—MS/MS and MS imaging were developed and used to screen the action targets related to NASH progress and treatment.A methionine and choline deficient(MCD)diet-induced mouse model of NASH was then constructed,and Schisandra lignans extract(SLE)was applied to alleviate hepatic damage by regulating the lipid metabolism-related enzymes CES2A and *** lipidomics indicated that MCD-diet led to aberrant accumulation of phosphatidylethanolamines(PEs),and SLE could significantly reduce the accumulation of intrahepatic ***,exogenous PE(18:0/18:1)was proved to significantly aggravate the mitochondrial damage and hepatocyte *** PE(18:0/18:1)also deteriorated the NASH progress by up regulating intrahepatic proinflammatory and fibrotic factors,while PE synthase inhibitor exerted a prominent hepatoprotective *** current work provides new insights into the relationship between PE metabolism and the pathogenesis of NASH.

关键词： Nonalcoholic steatohepatitis Multi-omics Schisandra lignans extract Phosphatidyle thanolamine PE(18:0/18:1)

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Three new bioactive flavonoid glycosides from Viscum album

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Chinese Journal of Natural Medicines 2019年第7期17卷 545-550页

作者： DAI Jia-Kun CAO Duo LI Cui-Hua GAO Jing LI Meng-Qing FAN Na WEI Ya-Hui SUN Zheng-Liang HOU Meng-Yang The College of Life Science Northwest University Xi 'an 710069 China state key laboratory of new drug and pharmaceutical process Shanghai Institute of Pharmaceutical Industry China State Institute of Pharmaceutical Industry Shanghai 201203 China The College of Life Science Yan 'an University Yan 'an 710000 China Shanghai University of Medicine & Health Sciences Affiliated Sixth People s Hospital South Campus Shanghai 201499 China Bio-Agriculture Institute of Shaanxi Xi 'an 710043 China School of Life Science and Biotechnology Dalian University of Technology Dalian 116024 China College of Healthy Management Shangluo University Shangluo 726000 China

Two new flavonoid glycosides, named viscumneoside XⅡ(1), and viscumneoside XⅢ(2);a new dihydrogen flavonoid glycoside product named viscumneoside XⅣ(3), were isolated from the aerial part of Viscum album, along with seven known compounds(4-10). Their structures were identified by analysis of spectroscopic data. In addition, cytotoxicity assay showed that 1, 2 and 3 possessed significant inhibitory activities against C6, A549 and MDA-MB-231(the inhibition rate arrived about 50%, 70% and74% respectively with IC50 ≤ 60.00 μmol·L^-1), while the inhibition of TF-1 and Hela was not significant.

关键词： Viscum album Flavonoid glycosides Cytotoxic activities

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Testis Specific Serine/Threonine Protein Kinase 4(TSSK4) Leads to Cell Apoptosis Relying on Its Kinase Activity

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2015年第2期35卷 235-240页

作者：王晓莉韦有衡付国龙余龙 state key laboratory of Genetic Engineering Institute of GeneticsSchool of Life SciencesFudan University key laboratory of Combinatorial Biosynthesis and drug Discovery (Wuhan University) Ministry of EducationWuhan University School of Pharmaceutical Sciences

Testis specific serine/threonine protein kinase 4（TSSK4） belongs to the TSSK family, and its members play an important role in spermatogenesis and/or spermiogenesis. Mouse TSSK4 has been reported to be expressed exclusively in the testis and can maintain its kinase activity through autophosphorylation at Thr-197. However, its biological function remains poorly understood. Here we found that GFP-TSSK4-overexpressed He La cells showed apoptotic bodies, indicating TSSK4 can lead to apoptosis in vitro. Furthermore, TSSK4 induced apoptosis in different cell lines including He La, Cos-7 and H1299 tested by flow cytometry but not its kinase-dead mutant TSSK4-K54 M. TSSK4 knockout mice showed increased testes weight and decreased apoptotic spermatogonia and spermatocytes at 21 st day after birth tested by TUNEL technology. So TSSK4 was able to induce cell apoptosis in vitro depending on its kinase activity, which leads to abnormal testes weight and apoptosis, shedding light on its function in the process of spermatogenesis and/or spermiogenesis.

关键词： Kinase Apoptosis cytometry understood testis poorly maintain mutant belongs threonine

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Predicting MDCK cell permeation coefficients of organic molecules using membrane-interaction QSAR analysis

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Acta Pharmacologica Sinica 2005年第11期26卷 1322-1333页

作者： Li-li CHEN, Jia YAO, Jian-bo YANG, Jie YANG~2 state key laboratory of pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China state key laboratory of pharmaceutical Biotechnology College of Life Sciences Nanjing University Nanjing China

Aim: To use membrane-interaction quantitative structure-activity relationship analysis (MI-QSAR) to develop predictive models of partitioning of organic compounds in gastrointestinal cells. Methods: A training set of 22 structurally diverse compounds, whose apparent permeability accross cellular membranes of Madin-Darby canine kidney (MDCK) cells were measured, were used to construct MI-QSAR models. Molecular dynamic simulations were used to determine the explicit interaction of each test compound (solute) with a dimyristoyl-phosphatidyl-cho-line monolayer membrane model. An additional set of intramolecular solute descriptors were computed and considered in the trial pool of descriptors for building MI-QSAR models. The QSAR models were optimized using multidimensional linear regression fitting and the stepwise method. A test set of 8 compounds were evaluated using the MI-QSAR models as part of a validation process. Results: MI-QSAR models of the gastrointestinal absorption process were constructed. The descriptors found in the best MI-QSAR models are as follows: 1) ClogP (the logarithm of the 1-octanol/water partition coefficient); 2) EHOMO(the highest occupied molecular orbital energy); 3) Es(stretch energy); 4) PMY(the principal moment of inertia Y, the inertia along the y axis in the rectangular coordinates; 5) C,(total connectivity); and 6) Enb(the energy of interactions between all of the non-bonded atoms). The most important descriptor in the models is ClogP. Conclusion: Permeability is not only determined by the properties of drug molecules, but is also very much influenced by the molecule-membrane interaction process.

关键词： quantitative structure-activity relationship molecular models organic chemicals artificial membranes cell membrane permeability MDCK cells

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Insight into the deamination mechanism of 6-cyclopropylamino guanosine analogs for anti-HIV drug design

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Chinese Chemical Letters 2016年第12期27卷 1759-1762页

作者： Xin-Meng Fan Xian-Tao Yang Yu-Jia Guo Ren-Min Wu De-Lin Pan Zhu Guan Xiao-Mei Ling Li-He Zhang Zhen-Jun Yang state key laboratory of Natural and Biomimetic drugs School of Pharmaceutical Sciences Peking University

Deamination is a crucial step in the transformation of 6-cyclopropylamino guanosine prodrug to its active form. A convenient method using capillary electrophoresis （CE） without sample labeling was developed to analyze the deamination of a series of D-/L-6-cyclopropylamino guanosine analogs by mouse liver homogenate, mouse liver microsome, and adenosine deaminase （ADA）. A two-step process involving a 6-amino guanosine intermediate formed by oxidative N-dealkylation was demonstrated in the metabolism of 6-cyclopropylamino guanosine to 6-hydroxy guanosine. The results indicated that the transformation rates of different prodrugs to the active form varied greatly, which were closely correlated with the configuration of nucleosides and the structure of glycosyl groups. Most importantly, D-form analogs were metabolized much faster than their L-counterparts, thus clearly pointed out that compared to guanine, modification of glycosyl part might be a better choice for the development of L-Kuanosine analogs for the treatment of HIV,

关键词： Deamination 6-Cyclopropylamino guanosine Mouse liver homogenate Adenosine deaminase Anti-HIV drug design

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Comparative analysis of constitutes and metabolites for traditional Chinese medicine using IDA and SWATH data acquisition modes on LC-Q-TOF MS

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Journal of pharmaceutical Analysis 2020年第6期10卷 588-596页

作者： Dian Kang Qingqing Ding Yangfan Xu Xiaoxi Yin Huimin Guo Tengjie Yu He Wang Wenshuo Xu Guangji Wang Yan Liang key lab of drug Metabolism&Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityTongjiaxiang 24Nanjing210009PR China Department of Geriatric Oncology First Affiliated Hospital of Nanjing Medical University(Jiangsu People’s Hospital)No.300 Guangzhou RoadNanjing210029PR China

Identification of components and metabolites of traditional Chinese medicines(TCMs)employing liquid chromatography-quadrupole time-of-flight mass spectrometry(LC-Q-TOF MS)techniques with information-dependent acquisition(IDA)approaches is increasingly frequent.A current drawback of IDA-MS is that the complexity of a sample might prevent important compounds from being triggered in IDA *** window acquisition of all theoretical fragment-ion spectra(SWATH)is a dataindependent acquisition(DIA)method where the instrument deterministically fragments all precursor ions within the predefined m/z range in a systematic and unbiased ***,the superiority of SWATH on the detection of TCMs’components was firstly investigated by comparing the detection efficiency of SWATH-MS and IDA-MS data acquisition modes,and sanguisorbin extract was used as a mode *** optimizing the setting parameters of SWATH,rolling collision energy(CE)and variable Q1 isolation windows were found to be more efficient for sanguisorbin identification than the fixed CE and fixed Q1 isolation *** importantly,the qualitative efficiency of SWATH-MS on sanguisorbins was found significantly higher than that of IDA-MS data *** IDA mode,18 kinds of sanguisorbins were detected in sanguisorbin extract.A total of 47 sanguisorbins were detected when SWATH-MS was used under rolling CE and flexible Q1 isolation window ***,26 metabolites of sanguisorbins were identified in rat plasma,and their metabolic pathways could be deduced as decarbonylation,oxidization,reduction,methylation,and glucuronidation according to their fragmental ions acquired in SWATH-MS ***,SWATH-MS data acquisition could provide more comprehensive information for the component and metabolite identification for TCMs than IDA-MS.

关键词： LC-Q-TOF MS SWATH-MS IDA-MS Sanguisorbin extract Sanguisorbins

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Tetrahydroisoquinolines as novel histone deacetylase inhibitors for treatment of cancer

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Acta Pharmaceutica Sinica B 2016年第1期6卷 93-99页

作者： Danqi Chen Aijun Shen Guanghua Fang Hongchun Liu Minmin Zhang Shuai Tang Bing Xiong Lanping Ma Meiyu Geng Jingkang Shen Department of Medicinal Chemistry State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Science Division of Anti-tumor Pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences

Histone acetylation is a critical process in the regulation of chromatin structure and gene *** deacetylases(HDACs)remove the acetyl group,leading to chromatin condensation and transcriptional *** inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor *** paper describes our work on the structural determination and structure-activity relationship(SAR)optimization of tetrahydroisoquinoline compounds as HDAC *** compounds were tested for their ability to inhibit HDAC 1,3,6 and for their ability to inhibit the proliferation of a panel of cancer cell *** these,compound 82 showed the greatest inhibitory activity toward HDAC 1,3,6 and strongly inhibited growth of the cancer cell lines,with results clearly superior to those of the reference compound,vorinostat(SAHA).Compound 82 increased the acetylation of histones H3,H4 and tubulin in a concentration-dependent manner,suggesting that it is a broad inhibitor of HDACs.

关键词： Histone deacetylases inhibitor Anticancer Tetrahydroisoquinoline Structure–activity relationship

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Small molecule SMU-CX24 targeting toll-like receptor 3 counteracts inflammation:A novel approach to atherosclerosis therapy

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3667-3681页

作者： Xiaohong Cen Baoqu Wang Yuqing Liang Yanlin Chen Yu Xiao Shaohua Du Kutty Selva Nandakumar Hang Yin Shuwen Liu Kui Cheng Guangdong Provincial key laboratory of new drug Screening and state key laboratory of Organ Failure Research School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Musculoskeletal Oncology the Third Affiliated Hospital of Southern Medical UniversityGuangzhou 510642China School of pharmaceutical Sciences Beijing Advanced Innovation Center for Structural BiologyTsinghua-Peking Joint Center for Life SciencesTsinghua UniversityBeijing 100084China

Toll-like receptor 3(TLR3),as an important pattern recognition receptor(PRR),dominates the innate and adaptive immunity regulating many acute and chronic inflammatory *** is proved as an inflammatory disease,and inflammatory events involved in the entire process of initiation and ***,the contribution of TLR3 to atherosclerosis remains ***,we identified the clinical relevance of TLR3 upregulation and disease processes in human ***,activation of TLR3 also directly led to significant expression of atherogenic chemokines and adhesion ***,silencing TLR3 inhibited the uptake of oxLDL by macrophages and significantly reduced foam cell *** the aberrance in TLR3 functions on atherosclerosis progression,we hypothesized that TLR3 could serve as novel target for clinical atherosclerosis ***,we developed the novel ellipticine derivative SMU-CX24,which specifically inhibited TLR3(IC_(50)=18.87±2.21 nmol/L).In vivo,atherosclerotic burden was alleviated in Western diet fed ApoE^(−/−)mice in response to SMU-CX24 treatment,accompanying notable reductions in TLR3 expression and inflammation infiltration within atherosclerotic ***,for the first time,we revealed that pharmacological downregulation of TLR3 with specific inhibitor regenerated inflammatory environment to counteract atherosclerosis progression,thereby proposing a new strategy and probe for atherosclerosis therapy.

关键词： Toll-like receptor 3 Atherosclerosis Small molecule Inflammation Macrophage

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