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Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 proteineprotein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells

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Genes & Diseases 2022年第6期9卷 1674-1688页

作者： Shasha Cheng Guan-jun Yang Wanhe Wang dik-Lung Ma Chung-Hang Leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoTaipaMacao SARPR China Department of Chemistry Hong Kong Baptist UniversityKowloon TongHong Kong SARPR China Institute of Medical Research Northwestern Polytechnical UniversityXi’anShaanxi 710072PR China Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao SARPR China

Triple-negative breast cancer(TNBC)is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer *** epithelial emesenchymal transition(EMT)and cancer stem cells(CSCs)have been proposed as important mechanisms underlying TNBC ***9 is highly expressed in breast cancer,including TNBC,where it promotes EMT and induces cancer cell *** this study,we have identified a tetrahydroisoquinoline derivative(compound 1)as a potent and selective CDK9-cyclin T1 inhibitor via virtual ***,by targeting the ATP binding site,compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 proteineprotein interaction(PPI).Mechanistically,compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction,leading to reduced TNBC cell proliferation and *** date,compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin *** 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC *** work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.

关键词： Cancer stem cells CDK9-cyclin T1 Epithelial mesenchymal transition Proteineprotein interaction(PPI) Triple-negative breast cancer(TNBC)

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Development of an orally bioavailable selective inhibitor of the menin-MLL

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Genes & Diseases 2023年第5期10卷 1735-1738页

作者： Hai-jing Zhong Wanhe Wang Wei Zhou jia-Xin Liang Yung-Chi Cheng dik-Lung Ma Chung-Hang Leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SARChina Department of Chemistry Hong Kong Baptist UniversityKowloon TongHong Kong SARChina Department of Pharmacology Yale University School of MedicineNew HavenCT 06520USA Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao SARChina International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE) College of PharmacyJinan UniversityGuangzhouGuangdong 510632China

The protein–protein interaction between menin and mixed lineage leukemia(MLL)plays an important role in the development of human hepatocellular carcinogenesis(HCC)and is associated with poor prognosis of HCC patients.1,2 Hence,interrupting the menin-MLL interaction is an attractive strategy in cancer treatment,particularly for liver cancer.3,4 In this study,we identified complex C1 as the first rhodium(III)-based orally bioavailable selective inhibitor of the menin-MLL interaction for HCC.

关键词： MLL prognosis carcinogenesis

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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

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Virtual screening and optimization of typeⅡ inhibitors of jAK2 from a natural product library

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中国药理学与毒理学杂志 2015年第S1期29卷 98-99页

作者： dik-LungMA DanielShiu-HinCHAN GuoWEI Hai-jingZHONG HuiYANG LaiToLEUNG ElizabethA.GULLEN PaulineChIU Yung-ChiCHENG Chung-hangLEUNG Department of Chemistry Hong Kong Baptist University Hong Kong China Department of Chemistry and the State Key Laboratory of Synthetic Chemistry University of Hong Kong Hong Kong China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA

OBjECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of jAK2 using the DOLPHIN *** Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of jAK2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in *** novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for jAK2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral *** The top eleven highest-scoring compounds were generated from the initial high-throughput virtual *** 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological *** dose-response experiments,amentoflavone 1ainhibited jAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·*** a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of *** octyl(C8)analogue 1bdisplayed superior potency against jAK2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this ***,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of *** Amentoflavone 1ahas been identified as a jAK2 inhibitor by structure-based virtual screening of a natural product *** silico optimization using the DOLPHIN model yielded analogues with enhanced potency against jAK2 activity and HCV activity in *** modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of jAK2.

关键词： jAK2 natural products virtual screening structure-

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Recent advances in the managements of type 2 diabetes mellitus and natural hypoglycemic substances

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Food Science and Human Wellness 2022年第5期11卷 1121-1133页

作者： Chong Ning Yuhan jiao jiaqi Wang Weiwei Li jingqiu Zhou Yi-Chieh Lee dik-Lung Ma Chung-Hang Leung Rugang Zhu Hui-Min David Wang College of Light Industry Liaoning UniversityShenyang 110036China Department of Life Sciences National Chung Hsing UniversityTaichung 402TaiwanChina Department of Chemistry Hong Kong Baptist UniversityKowloon Tong 999077Hong KongChina State Key Laboratoryof Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China Graduate Institute of Biomedical Engineering National Chung Hsing UniversityTaichung 402TaiwanChina Graduate Institute of Medicine College of MedicineKaohsiung Medical UniversityKaohsiung City 807TaiwanChina Department of Medical Laboratory Science and Biotechnology China Medical UniversityTaichung City 404TaiwanChina

Diabetes has become a global concern at present,among which type 2 diabetes mellitus(T2DM)accounts for approximately 90%-95%of patients.T2DM is a type of metabolic disorder syndrome that results from a genetic defect,and it is based on insulin resistance and an insulin secretion *** occurrence of T2DM is usually the outcome of both genetic and environmental factors and their *** etiology and pathogenesis of diabetes have not been fully elucidated,and no radical therapeutic cure has been *** with T2DM suffer from complications such as the development of a chronic hyperglycemic condition and even serious metabolic disorders and organ damage in the body and depression and dementia,in addition to other chronic *** studies have suggested that diet is crucial in the development of diabetes and the control of blood *** substances have the characteristics of low toxicity and few side effects and may be key to the development of diabetic health products and preventive *** paper reviews the etiology,pathogenesis,risks,treatments and diets related to T2DM to summarize the types of recently available natural products,from both local and foreign sources,for lowering blood glucose at home and their application in supplementary hypoglycemic *** key findings and conclusions suggest that there are various known T2DM-inducing factors,including genetic and environmental factors and three types of hybrid factors.

关键词： Obesity Type 2 diabetes mellitus Etiological agent Diet Insulin resistance Natural substances

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一元店的杀手锏

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商周刊 2017年第5期 46-47页

作者： dik

这家全美最大的连锁社区超市,以“1元店”著称,年开店13000家,盈利能力围剿沃尔玛.2016年,零售巨头沃尔玛宣布要在美国关店269家,其中包括沃尔玛从2011年开始的102家社区门店Walmart Express.在这102家社区超市中,有41家店被一个小型超...

这家全美最大的连锁社区超市,以“1元店”著称,年开店13000家,盈利能力围剿沃尔玛.2016年,零售巨头沃尔玛宣布要在美国关店269家,其中包括沃尔玛从2011年开始的102家社区门店Walmart Express.在这102家社区超市中,有41家店被一个小型超市的连锁公司收购了.这个连锁超市名叫Dollar General,1美元杂货店.

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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

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爆炸载荷下油罐钢板破损的数值模拟

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水运工程 2007年第9期 23-26页

作者：秦小勇赵铮 dik.voerman 李晓杰大连理工大学土木工程学院岩土工程研究所大连理工大学工程力学系工业装备结构分析国家重点实验室辽宁大连116024 大连港湾储罐码头有限公司辽宁大连116001

目前国内外学者日益重视大型储油罐区的安全问题,油罐的防爆炸破坏能力成为研究的热点之一。利用LS-DYNA有限元程序,模拟了油罐钢板在3#岩石炸药爆炸载荷下的破坏过程,分析了炸药质量、药柱形状对钢板破坏程度和破口形状的影响。由于药... 详细信息

目前国内外学者日益重视大型储油罐区的安全问题,油罐的防爆炸破坏能力成为研究的热点之一。利用LS-DYNA有限元程序,模拟了油罐钢板在3#岩石炸药爆炸载荷下的破坏过程,分析了炸药质量、药柱形状对钢板破坏程度和破口形状的影响。由于药柱形状规则,钢板主要发生类似冲孔的剪切破坏,破坏程度随炸药质量的增加而加强,爆轰产物会从钢板破口处进入油罐内部。

关键词：油罐接触爆炸数值模拟 LS-DYNA

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基于LS-DYNA强夯冲击数值模拟

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水运工程 2007年第9期 31-35页

作者：秦小勇李晓杰 dik.voerman 赵铮徐涛大连理工大学土木工程学院岩土工程研究所大连理工大学力学系辽宁大连116024 大连港湾储罐码头有限公司辽宁大连116001

针对强夯过程中,在夯击点及其周围存在局部大变形现象,采用大变形理论对强夯振动进行分析,并利用LS-DYNA有限元软件对强夯过程中土体变形的瞬态过程进行数值模拟,得到的速度时程数据与实际测量的数据比较接近。采用量纲分析的方法得到... 详细信息

针对强夯过程中,在夯击点及其周围存在局部大变形现象,采用大变形理论对强夯振动进行分析,并利用LS-DYNA有限元软件对强夯过程中土体变形的瞬态过程进行数值模拟,得到的速度时程数据与实际测量的数据比较接近。采用量纲分析的方法得到质点垂直振动速度与距离和夯锤重量的关系式,根据实测数据拟合出真实场地上振动速度的关系,拟合公式为预测强夯振动提供了一个新方法,对预测类似工程因强夯产生的振动对相邻建构筑物的影响有一定的指导意义。

关键词：强夯大变形振动 LS-DYNA数值模拟

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油品及化工品铁路装卸栈台鹤位探讨

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水运工程 2007年第9期 27-30页

作者：秦小勇 dik.voerman 张保义刘文勇大连理工大学土木工程学院岩土工程研究所大连港湾储罐码头有限公司辽宁大连1160001

对目前油品及化工品铁路装卸栈台鹤位的现状进行分析,结合大连东港区液体化工搬迁建设工程铁路装卸栈台工程的实践,认为对易燃、有毒、批量小、质量要求、商品价值高、工艺复杂、管线细而多的液体化工品铁路装卸栈台,推荐使用软管架式... 详细信息

对目前油品及化工品铁路装卸栈台鹤位的现状进行分析,结合大连东港区液体化工搬迁建设工程铁路装卸栈台工程的实践,认为对易燃、有毒、批量小、质量要求、商品价值高、工艺复杂、管线细而多的液体化工品铁路装卸栈台,推荐使用软管架式的小吊鹤位装卸车臂技术;而对品种单一、批量大的油品,建议使用鹤管装卸车技术;对易挥发、蒸汽压高的介质,建议使用鹤管-潜液泵技术。通过实践,对规范和教科书中鹤位间距的模糊描述予以了纠正。

关键词：油品化工品小吊鹤位鹤管潜液泵真空装卸工艺

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