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Virtual screening and optimization of typeⅡ inhibitors of JAK2 from a natural product library

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 protocol.METHODS 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 silico.The 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 activity.RESULTS The top eleven highest-scoring compounds were generated from the initial high-throughput virtual screening.Amentoflavone 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological evaluation.In dose-response experiments,amentoflavone 1ainhibited JAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·L-1.As 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 1a.The 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 study.Moreover,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of JAK2.CONCLUSION Amentoflavone 1ahas been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library.In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo.Molecular 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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Effcacy of Yisui granule (益髓颗粒) on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/β-catenin signaling pathway

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Journal of Traditional Chinese Medicine 2023年

作者： WU Jieya HOU Li ZHANG Xiaoyuan Elizabeth gullen GAO Chong WANG Jing Department of Pharmacology Yale Medical School Department of Oncology and Hematology Dongzhimen Hospital Beijing University of Chinese Medicine Department of Oncology Beijing Hospital of Traditional Chinese Medicine Capital Medical University

OBJECTIVE: To unmask the underlying mechanisms of Yisui granule (益髓颗粒， YSG) for the treatment of Myelodysplastic syndromes (MDS). METHODS: Our study used an SKM-1 mouse xenograft model of MDS to explore the anti-tumor potential of YSG and its safety， assess its effect on overall survival (OS)， and evaluate whether its mechanism is associated with the demethylation of the secreted frizzled related protein 5 (sFRP5) gene and suppressing Wnt/β-catenin pathway. Bisulfite amplicon sequencing was applied to detect the level of methylation of the sFRP5 gene; western blotting， immunofluorescence staining， and real-time Polymerase Chain Reaction were performed to detect DNA methyltransferase 1 (DNMT1)， sFRP5， and other Wnt/β-catenin pathway-related mRNA and protein expression. RESULTS: The results showed that high-dosage YSG exerted an anti-tumor effect similar to that of decitabine， improved OS， and reduced long-term adverse effects in the long term. Mechanically， YSG reduced the expression of DNMT1 methyltransferase， decreased the methylation， and increased the expression of the Wnt/β-catenin pathway antagonist-sFRP5. Furthermore， components of the Wnt/β-catenin pathway， including Wnt3a， β-catenin， c-Myc， and cyclinD1， were down-regulated in response to YSG， suggesting that YSG could treat MDS by demethylating the sFRP5 gene and suppressing the Wnt/β-catenin pathway. CONCLUSIONS: Our findings demonstrated that YSG could be used alone or in combination with decitabine to improve outcomes in the MDS animal model， providing an alternative solution for treating MDS.

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Efficacy of Yisui granule(益髓颗粒)on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/β-catenin signaling pathway

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Journal of Traditional Chinese Medicine 2024年第1期44卷 78-87页

作者： WU Jieya HOU Li ZHANG Xiaoyuan Elizabeth gullen GAO Chong WANG Jing Department of Oncology and Hematology Dongzhimen HospitalBeijing University of Chinese MedicineBeijing 100700China Department of Pharmacology Yale Medical SchoolNew HavenCT 06510USA Department of Oncology Beijing Hospital of Traditional Chinese MedicineCapital Medical UniversityBeijing 100010China

OBJECTIVE:To unmask the underlying mechanisms of Yisui granule(益髓颗粒,YSG)for the treatment of Myelodysplastic syndromes(MDS).METHODS:Our study used an SKM-1 mouse xenograft model of MDS to explore the anti-tumor potential of YSG and its safety,assess its effect on overall survival(OS),and evaluate whether its mechanism is associated with the demethylation of the secreted frizzled related protein 5(s FRP5)gene and suppressing Wnt/β-catenin pathway.Bisulfite amplicon sequencing was applied to detect the level of methylation of the s FRP5 gene;western blotting,immunofluorescence staining,and real-time Polymerase Chain Reaction were performed to detect DNA methyltransferase 1(DNMT1),s FRP5,and other Wnt/β-catenin pathway-related m RNA and protein expression.RESULTS:The results showed that high-dosage YSG exerted an anti-tumor effect similar to that of decitabine,improved OS,and reduced long-term adverse effects in the long term.Mechanically,YSG reduced the expression of DNMT1 methyltransferase,decreased the methylation,and increased the expression of the Wnt/β-catenin pathway antagonist-s FRP5.Furthermore,components of the Wnt/β-catenin pathway,including Wnt3a,β-catenin,c-Myc,and cyclin D1,were down-regulated in response to YSG,suggesting that YSG could treat MDS by demethylating the s FRP5 gene and suppressing the Wnt/β-catenin pathway.CONCLUSIONS:Our findings demonstrated that YSG could be used alone or in combination with decitabine to improve outcomes in the MDS animal model,providing an alternative solution for treating MDS.

关键词： myelodysplastic syndromes Wnt signaling pathway beta catenin decitabine survival adverse effects sFRP5 gene methylation Yisui granule

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科尔沁左翼后旗土地利用结构特征分析

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中国资源综合利用 2020年第2期38卷 81-83页

作者：乌吉斯古楞内蒙古师范大学地理科学学院呼和浩特010022

本文以科尔沁左翼后旗2009-2017年的土地利用数据为基础,运用土地利用动态度模型、土地利用程度综合指数以及土地利用结构信息熵模型,分析了该旗将近九年的土地利用结构变化特征。结果表明,2009-2017年,科尔沁左翼后旗土地利用类型以耕... 详细信息

本文以科尔沁左翼后旗2009-2017年的土地利用数据为基础,运用土地利用动态度模型、土地利用程度综合指数以及土地利用结构信息熵模型,分析了该旗将近九年的土地利用结构变化特征。结果表明,2009-2017年,科尔沁左翼后旗土地利用类型以耕地、草地及林地为主,其中耕地、城镇用地、交通用地面积持续增加,林地、草地及其他土地面积下降,而园地和水域用地无明显变化。

关键词：科尔沁左翼后旗土地利用结构信息熵

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