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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

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

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

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

HM30181A,a potent P-glycoprotein inhibitor,potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model

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Cancer Biology & Medicine 2020年第4期17卷 986-1001页

作者： Wu Zeng Betty Yuen Kwan Law vincent kam wai wong Denise So Bik Chan Simon Wing Fai Mok Joyce Jia Ying Gao Rebecca Ka Yan Ho Xu Liang Jia Hao Li Ming Tsung Lee Weng Li Yoon Michael P Smolinski Johnson Yiu Nam Lau Christopher wai Kei Lam Manson Fok State Key Laboratory of Quality Research in Chinese Medicines Macao University of Science and TechnologyMacaoChina At he nex Hong Kong Irmo vative Limited Hong Kong China Faculty of Medici ne Macao Un iversity of Science and TechnologyMacaoChina Athenex Inc. New York 14203USA

Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic *** aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant ***:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer *** and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse ***:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did *** study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this ***-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.

关键词： HM30181A glioma pharmacokinetics paclitaxel P-glycoprotein

Natural Alkaloids Induce Autophagy and Autophagy Cell Death in Apoptosis-resistant Cells

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Natural Alkaloids Induce Autophagy and Autophagy Cell Death ...

Identification of Herb A as a Neuroprotective Autophagy Inducer By Using Cell Membrane Chromatography and LC/MS-TOF

第十四届全国中药和天然药物学术研讨会

作者： Betty Yuen Kwan Law Liang Liu vincent kam wai wong Macau University of Science and Technology

＜正＞Drug-resistance of cancer cells to chemotherapy is a significant problem in cancer therapy,and the development of sensitising agents or small-molecules with new mechanisms of action to kill these cells is highly *** is a cellular process responsible for the turnover of misfolded proteins or damaged organelles,and it also recycles nutrients to

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Identification of Herb A as a Neuroprotective Autophagy Indu...