In the context of today's big data and cloud computing,the global flow of data has become a powerful driver for international economic and investment growth.The EU and the U.S.have created two different paths for ...In the context of today's big data and cloud computing,the global flow of data has become a powerful driver for international economic and investment growth.The EU and the U.S.have created two different paths for the legal regulation of the cross-border flow of personal data due to their respective historical traditions and realistic demands.The requirements for data protection have shown significant differences.The EU advocates localization of data and firmly restricts cross-border flow of personal data.The U.S.tends to protect personal data through industry self-regulation and government law enforcement.At the same time,these two paths also merge and supplement with each other.Based on this,China needs to learn from the legal regulatory paths of the EU and the US,respectively,to establish a legal idea that places equal emphasis on personal data protection and the development of the information industry.In terms of domestic law,the Cybersecurity Law of the People's Republic of China needs to be improved and supplemented by relevant supporting legislation to improve the operability of the law;the industry self-discipline guidelines should be established;and various types of cross-border data need to be classified and supervised.In terms of international law,it is necessary to participate in international cooperation based on the priority of data sovereignty and promote the signing of bilateral,multilateral agreements,and international treaties on the cross-border flow of personal data.展开更多
Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. ...Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u also showed strong antiproliferative activity against four leukemia cell lines(OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.展开更多
Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clin...Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clinical trials.In this work,a focused library of new [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4.WS-722 inactivated BRD4(BD1/BD2),BRD2(BD1/BD2) and BRD3(BD1/BD2) broadly with the IC_(50) values less than 5 μmol/L.Besides,WS-722 inhibited growth of THP-1 cells with an IC_(50) value of 3.86 μmol/L.Like(+)-JQ1,WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability.Docking studies showed that WS-722 occupied the central acetyl-lysine(Kac) binding cavity and formed a hydrogen bond with Asn140.In THP-1 cells,WS-722 showed target engagement to BRD4.Cellular effects of WS-722 on THP-1 cells were also examined,showing that WS-722 could block c-MYC expression,induce G0/G1 phase arrest and p21 up-regulation,and promote differentiation of THP-1 cells.BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines.The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.展开更多
基金This article is supported by Law and Technology Institute,Renmin University of China.All mistakes and omissions are the responsibility of the author.
文摘In the context of today's big data and cloud computing,the global flow of data has become a powerful driver for international economic and investment growth.The EU and the U.S.have created two different paths for the legal regulation of the cross-border flow of personal data due to their respective historical traditions and realistic demands.The requirements for data protection have shown significant differences.The EU advocates localization of data and firmly restricts cross-border flow of personal data.The U.S.tends to protect personal data through industry self-regulation and government law enforcement.At the same time,these two paths also merge and supplement with each other.Based on this,China needs to learn from the legal regulatory paths of the EU and the US,respectively,to establish a legal idea that places equal emphasis on personal data protection and the development of the information industry.In terms of domestic law,the Cybersecurity Law of the People's Republic of China needs to be improved and supplemented by relevant supporting legislation to improve the operability of the law;the industry self-discipline guidelines should be established;and various types of cross-border data need to be classified and supervised.In terms of international law,it is necessary to participate in international cooperation based on the priority of data sovereignty and promote the signing of bilateral,multilateral agreements,and international treaties on the cross-border flow of personal data.
基金supported by the National Key Research Program of Proteins(Nos.2016YFA0501800 and 2017YFD0501401,China)the National Natural Science Foundation of China(Nos.81703326,81773562,81430085 and 21403200,China)+5 种基金the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nan-jing University,China(No.KF-GN-201902,China)Outstanding Young Talent Research Fund of Zhengzhou University(No.1521331002,China)Scientific Program of Henan Province(Nos.182102310123 and 161100310100,China)China Postdoctoral Science Foundation(No.2018M630840,China)Key Research Program of Higher Education of Henan Province(Nos.15A350018 and 18B350009,China)the Starting Grant of Zhengzhou University(No.32210533,China)
文摘Histone lysine specific demethylase 1(LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8 a(IC50=3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15 u(IC50=49 nmol/L, and Ki= 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3 K4 me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency ofcompound 15 u. Compound 15 u also showed strong antiproliferative activity against four leukemia cell lines(OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15 u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15 u induced expression of CD86 and CD11 b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazolefused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1 A inhibitors.
基金supported by the National Natural Science Foundation of China(Nos.81703326,81773562,81602961 and 81430085)Scientific Program of Henan Province(No.182102310123)China Postdoctoral Science Foundation(Nos.2018M630840 and 2019T120641)。
文摘Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clinical trials.In this work,a focused library of new [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4.WS-722 inactivated BRD4(BD1/BD2),BRD2(BD1/BD2) and BRD3(BD1/BD2) broadly with the IC_(50) values less than 5 μmol/L.Besides,WS-722 inhibited growth of THP-1 cells with an IC_(50) value of 3.86 μmol/L.Like(+)-JQ1,WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability.Docking studies showed that WS-722 occupied the central acetyl-lysine(Kac) binding cavity and formed a hydrogen bond with Asn140.In THP-1 cells,WS-722 showed target engagement to BRD4.Cellular effects of WS-722 on THP-1 cells were also examined,showing that WS-722 could block c-MYC expression,induce G0/G1 phase arrest and p21 up-regulation,and promote differentiation of THP-1 cells.BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines.The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.
