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Development of a dual targeting scaffold of SET7/MLL inhibitor for castration-resistant prostate cancer treatment

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Genes & Diseases 2023年第6期10卷 2260-2262页

作者： Guodong Li Qi Huang vincent kam wai wong Wanhe Wang Chung-Hang Leung Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine University of MacaoMacao SAR 999078China Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao SAR 999078China Institute of Medical Research Northwestern Polytechnical UniversityXi'anShaanxi 710072China Macao Centre for Research and Development in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SAR 999078China Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao SAR 999078China Zhuhai UM Science and Technology Research Institute ZhuhaiGuangdong 519000China

Histone methyltransferase enzyme SET7 and mixed-lineage leukemia protein(MLL)complex are crucial co-activators of androgen receptor(AR)and have recently emerged as potential therapeutic targets for advanced castration-resistant prostate cancer(CRPC).In this study,we described the identification of a rhodium-based hybrid complex(SM_1)as a potent blocker of AR activity via simultaneously inhibiting SET7 and MLL complex activity,which makes it a potential lead scaffold for CPRC drug development.

关键词： cancer inhibiting treatment

A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance

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Journal of Pharmaceutical Analysis 2023年第5期13卷 514-522页

作者： Ying-Qi Song Guo-Dong Li Dou Niu Feng Chen Shaozhen Jing vincent kam wai wong Wanhe Wang Chung-Hang Leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao999078China Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao999078China Institute of Medical Research Northwestern Polytechnical UniversityXi'an710072China Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao999078China

Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical ***,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA *** have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine lesions,is overexpressed in glioblastoma tissues compared to normal ***,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in ***,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic *** a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG *** restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell characteristics,and induced GBM cell cycle ***,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.

关键词： Drug screening Alkyladenine DNA glycosylase N3-methyladenine Glioblastoma Temozolomide Sunitinib

The potential development of drug resistance in rheumatoid arthritis patients identified with p53 mutations

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Genes & Diseases 2023年第6期10卷 2252-2255页

作者： Congling Qiu Joyce Tsz wai Chan David Wei Zhang Io Nam wong Yaling Zeng Betty Yuen Kwan Law Simon Wing Fai Mok Ivo Ricardo De Seabra Rodrigues Dias Wenfeng Liu Liang Liu vincent kam wai wong Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao SAR 999078China Department of Public Health and Preventive Medicine School of MedicineJinan UniversityGuangzhouGuangdong 510000China Faculty of Medicine Macao University of Science and TechnologyMacao SAR 999078China School of Biotechnology and Health Sciences Wuyi UniversityJiangmenGuangdong 529000China

Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by cartilage and bone damage with the presence of pannus formation which causes uncontrollable proliferation and invasion of fibroblast-like synoviocytes(FLS).Since rheumatoid arthritis is a chronic disorder,the patients normally need to undergo prolonged antirheumatic treatment with the use of disease-modifying antirheumatic drugs(DMARDs),steroids,and nonsteroidal anti-inflammatory drugs(NSAIDs).The efficacy of such long-term pharmaceutical intervention can be significantly affected by the development of drug *** pathological relationship between rheumatoid arthritis and cancer hinted that some chemotherapeutic drugs,such as methotrexate(MTX),could be used for RA *** idea was reinforced by the analysis of mutations in p53 tumor suppressor *** 50%of p53 somatic mutations observed from various cancers are also identified in the synovium of RA patients1(Fig.1A).Of note,the hyperplastic synovium in RA with overexpressed p53 mutants contributed to the destruction of joints in patients with erosive RA.

关键词： patients drugs rheumatoid

Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1390-1405页

作者： Sha-Sha Cheng Yuan-Qing Qu Jia Wu Guan-Jun Yang Hao Liu Wanhe Wang Qi Huang Feng Chen Guodong Li Chun-Yuen wong vincent kam wai wong Dik-Lung Ma Chung-Hang Leung Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine University of MacaoMacao 999078China Dr.Neher’s Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao 999078China State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityKow loon TongHong Kong 999077China Laboratory of Biochemistry and Molecular Biology School of Marine SciencesNingbo UniversityNingbo 315211China Department of Chemistry Hong Kong Baptist UniversityNingbo 315211China Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Department of Chemistry City University of Hong KongHong Kong 999077China Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao 999078China

Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative breast cancer(TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction(PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CN ligand and tested their activity against the CDK9cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

关键词： Metal complex Kinase inhibitor Protein-protein interaction Epigenetics Triple-negative breast cancer Metastasis

Aurone derivatives as Vps34 inhibitors that modulate autophagy

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Acta Pharmaceutica Sinica B 2019年第3期9卷 537-544页

作者： Guodong Li Joshua William Boyle Chung-Nga Ko Wu Zeng vincent kam wai wong Jian-Bo Wan Philip wai Hong Chan Dik-Lung Ma Chung-Hang Leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao999078China School of Chemistry Monash UniversityClayton3800Australia Department of Chemistry Hong Kong Baptist UniversityHong Kong999077China State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacao999078China Department of Chemistry University of WarwickCoventry CV47ALUK

We report in this study the identification of a natural product-like antagonist(1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mT OR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.

关键词： Autophagy Natural products Vps34 Inhibitor Structure-based virtual screening Vesicle trafficking Heart or liver damage Aurone derivative

Insights on advanced substrates for controllable fabrication of photoanodes toward efficient and stable photoelectrochemical water splitting

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Carbon Energy 2024年第4期6卷 164-221页

作者： Huilin Hou Gang Shao Yang Wang wai‐Yeung wong Weiyou Yang Institute of Micro/Nano Materials and Devices Ningbo University of TechnologyNingboChina School of Materials Science and Engineering Zhengzhou UniversityZhengzhouChina Department of Applied Biology and Chemical Technology and Research Institute for Smart Energy The Hong Kong Polytechnic UniversityHong KongChina

Conversion of solar energy into H_(2) by photoelectrochemical(PEC)water splitting is recognized as an ideal way to address the growing energy crisis and environmental *** a typical PEC cell,the construction of photoanodes is crucial to guarantee the high efficiency and stability of PEC reactions,which fundamentally rely on rationally designed semiconductors(as the active materials)and substrates(as the current collectors).In this review work,we start with a brief introduction of the roles of substrates in the PEC ***,we provide a systematic overview of representative strategies for the controlled fabrication of photoanodes on rationally designed substrates,including conductive glass,metal,sapphire,silicon,silicon carbide,and flexible ***,some prospects concerning the challenges and research directions in this area are proposed.

关键词： hydrogen photoanode photoelectrochemical substrates water splitting

Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 241-248页

作者： Chao Sun George Boon-Bee Goh Wan-Cheng Chow Wah-Kheong Chan Grace Lai-Hung wong wai-Kay Seto Yi-Hsiang Huang Han-Chieh Lin I-Cheng Lee Hye Won Lee Seung Up Kim vincent wai-Sun wong Jian-Gao Fan Center for Fatty Liver Disease Department of GastroenterologyXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Key Lab of Pediatric Gastroenterology and NutritionShanghai 200092China Department of Gastroenterology&Hepatology Singapore General HospitalSingaporeSingapore Gastroenterology and Hepatology Unit Department of MedicineFaculty of MedicineUniversity of MalayaKuala LumpurMalaysia Department of Medicine and Therapeutics and State Key Laboratory of Digestive Disease The Chinese University of Hong KongHong KongChina Department of Medicine The University of Hong KongHong KongChina Institute of Clinical Medicine National Yang Ming Chiao Tung University School of MedicineTaipeiTaiwanChina Division of Gastroenterology and Hepatology Taipei Veterans General HospitalTaipeiTaiwanChina Faculty of Medicine National Yang Ming Chiao Tung University School of MedicineTaipeiTaiwanChina Department of Internal Medicine Yonsei University College of MedicineSeoulKorea

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic ***,the prevalence and risk factors for impaired renal function in patients with NAFLD remain *** objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD ***:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective *** fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 *** renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value of<90 mL/min/1.73 m^(2) and<60 mL/min/1.73 m^(2),respectively,as estimated by the CKD-Epidemiology Collaboration(CKD-EPI)***:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,*** multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of *** glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

关键词： Nonalcoholic fatty liver disease Impaired renal function Agile 3+ Agile 4 Metabolic syndrome

Cellular zinc metabolism and zinc signaling:from biological functions to diseases and therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 401-441页

作者： Bonan Chen Peiyao Yu wai Nok Chan Fuda Xie Yigan Zhang Li Liang kam Tong Leung Kwok wai Lo Jun Yu Gary M.K.Tse Wei Kang Ka Fai To Department of Anatomical and Cellular Pathology State Key Laboratory of Translational OncologyPrince of Wales HospitalThe Chinese University of Hong KongHong KongChina State Key Laboratory of Digestive Disease Institute of Digestive DiseaseThe Chinese University of Hong KongHong KongChina CUHK-Shenzhen Research Institute The Chinese University of Hong KongShenzhenChina Department of Pathology Nanfang Hospital and Basic Medical CollegeSouthern Medical UniversityGuangdong Province Key Laboratory of Molecular Tumor PathologyGuangzhouChina Institute of Biomedical Research Taihe HospitalHubei University of MedicineShiyanChina Department of Pediatrics The Chinese University of Hong KongHong KongChina Department of Medicine and Therapeutics The Chinese University of Hong KongHong KongChina

Zinc metabolism at the cellular level is critical for many biological processes in the body.A key observation is the disruption of cellular homeostasis,often coinciding with disease *** an essential factor in maintaining cellular equilibrium,cellular zinc has been increasingly spotlighted in the context of disease *** research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells,despite its low tissue *** has led to a growing body of literature investigating zinc’s cellular metabolism,particularly the functions of zinc transporters and storage mechanisms during cancer *** transportation is under the control of two major transporter families:SLC30(ZnT)for the excretion of zinc and SLC39(ZIP)for the zinc ***,the storage of this essential element is predominantly mediated by metallothioneins(MTs).This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression,with a special focus on *** also compile a summary of clinical trials involving zinc *** the main localization of zinc transporters at the cell membrane,the potential for targeted therapies,including small molecules and monoclonal antibodies,offers promising avenues for future exploration.

关键词： metabolism invasion involvement

Targeting autophagy as a therapeutic strategy for identification of liganans from Peristrophe japonica in Parkinson’s disease

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Signal Transduction and Targeted Therapy 2021年第3期6卷 596-598页

作者： An-Guo Wu Rong Pan Betty Yuen-Kwan Law Wen-Qiao Qiu Jian-Ming Wu Chang-Long He vincent kam-wai wong Chong-Lin Yu Xiao-Gang Zhou Da-Lian Qin Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaSchool of PharmacyDepartment of Human AnatomySchool of Preclinical MedicineEducation Ministry Key Laboratory of Medical ElectrophysiologySouthwest Medical UniversityLuzhou 646000China State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacaoChina

Dear Editor,PD is characterized by the loss of dopaminergic neurons in substantia nigra,and the loss of dopamine resulting in motor deficit.1 Its main pathological hallmarks include the genetic mutations of gene such as a-synudein.2 Increasing study showed that the dopaminergic neurons in midbrain are sensitive and damaged by the PD toxins.

关键词： nude dopamine therapeutic