Metformin is currently a strong candidate anti-tumor agent in multiple cancers.However,its anti-tumor effectiveness varies among different cancers or sub-populations,potentially due to tumor heterogeneity.It thus rema...Metformin is currently a strong candidate anti-tumor agent in multiple cancers.However,its anti-tumor effectiveness varies among different cancers or sub-populations,potentially due to tumor heterogeneity.It thus remains unclear which hepatocellular carcinoma(HCC)patient subpopulation(s)can benefit from met-formin treatment.Here,through a genome-wide CRISPR-Cas9-based knockout screen,we find that DOCK1 levels determine the anti-tumor effects of met-formin and that DOCK1 is a synthetic lethal target of metformin in HCC.Mechanistically,metformin promotes DOCK1 phosphorylation,which activates RAC1 to facilitate cell survival,leading to metformin resistance.The DOCK1-selective inhibitor,TBOPP,potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids,and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models.Notably,metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression.This study shows that metformin effective-ness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for met-formin-resistant HCC patients.展开更多
细胞质分裂付出蛋白1(dedicator of cytokinesis 1,DOCK1)作为Rho GTP酶家族的关键上游分子,在细胞迁移过程中发挥关键性的作用。细胞表面受体与配体结合后,通过一系列衔接蛋白招募并活化DOCK1蛋白,进而促进细胞生长和迁移等生物学过程...细胞质分裂付出蛋白1(dedicator of cytokinesis 1,DOCK1)作为Rho GTP酶家族的关键上游分子,在细胞迁移过程中发挥关键性的作用。细胞表面受体与配体结合后,通过一系列衔接蛋白招募并活化DOCK1蛋白,进而促进细胞生长和迁移等生物学过程。活化的DOCK1通过激活Rac1调节下游的肌动蛋白组装,从而影响细胞迁移、粘附和存活。DOCK1在癌细胞迁移和侵袭中的作用越来越受到重视。DOCK1在肺癌、膀胱癌、卵巢癌、急性髓系白血病等多种肿瘤中的过度表达与其预后差相关。DOCK1在肿瘤细胞的迁移、肿瘤血管生成以及肿瘤耐药方面发挥重要作用。提示DOCK1是一个治疗癌转移的可能靶点。展开更多
A series of 2-（arylmethylidene）-2,3-dihydro-1-benzofuran-3-one derivatives（aurones, 1–20） were synthesized and screened for their inhibitory activity against h MAO. Seventeen compounds（1–5, 7–17,19） were foun...A series of 2-（arylmethylidene）-2,3-dihydro-1-benzofuran-3-one derivatives（aurones, 1–20） were synthesized and screened for their inhibitory activity against h MAO. Seventeen compounds（1–5, 7–17,19） were found to be selective towards h MAO-B, while two were non-selective（6 and 20） and one（18）selective towards h MAO-A. Compound 17（Ki = 0.10 0.01 mmol/L） was found to be equally potent and selective towards h MAO-B, when compared with the standard drug Selegiline（Ki = 0.12 0.01 mmol/L）.Nature and position of substitution in aryl ring at 2nd position of benzofuranone influences h MAO-B inhibitory potency, while their structural bulkiness influences selectivity between h MAO-A and h MAO-B.Molecular docking simulation was also carried out to understand the interaction of inhibitor with the enzyme at molecular level, and we found the docking results were in good agreement with the experimental values. Comparison of the activity profile of the aurones with their corresponding flavones reported earlier by our group revealed that there exists no difference in potency as well as selectivity.展开更多
Highly Pathogenic Avian Influenza（HPAI） H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase（NA） has an important role in viral replicati...Highly Pathogenic Avian Influenza（HPAI） H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase（NA） has an important role in viral replication. Thus, it is an attractive target when designing anti-influenza virus drug. However, evolving viruses cause some anti-viral drugs to be ineffective, as they show resistance to them. Selection of peptides as drug candidates is important for the peptide-receptor activity and good selectivity. Cyclic bonds in the peptide ligand design aim to improve the stability of the system and remove the obstacles in drug metabolism. The design is based on the polarity of the ligand and amino acid residues in the active site of NA. The results are 4200 cyclic pentapeptides as potential lead compounds. Docking simulations were conducted using MOE 2008.10 and were screened based on the value of the binding energy（？Gbinding）. ADME-Tox prediction assay was conducted on the selected ligands.Intra- and inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312 K. The results of the docking simulations and toxicity prediction assay show that there are two ligands that have a residual interaction with the target protein： CLDRC and CIWRC. These two ligands have ？Gbindingvalues of –40.5854 and –39.9721 kcal/mol（1 kcal/mol = 4.18 k J/mol）. These ligands are prone to be mutagenic and carcinogenic, and they have a good oral bioavailability. The results show that the molecular dynamics of both ligand CLDRC and CIWRC are more feasible at the temperature of 312 K. At the end,both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.展开更多
基金supported in part by National Key R&D Program of China(2018YFA0107103,2018YFA0800300)the Chinese Academy of Sciences(XDB39000000)+3 种基金National Natural Science Foundation of China(81930083,91957203,81821001,81525022)Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR110102001)the Program for Guangdong Introducing Innovative and Entrepreneurial Teams(2017ZT07S054)the Fundamental Research Funds for the Central Universities(YD2070002008,2020ZYGXZR038).
文摘Metformin is currently a strong candidate anti-tumor agent in multiple cancers.However,its anti-tumor effectiveness varies among different cancers or sub-populations,potentially due to tumor heterogeneity.It thus remains unclear which hepatocellular carcinoma(HCC)patient subpopulation(s)can benefit from met-formin treatment.Here,through a genome-wide CRISPR-Cas9-based knockout screen,we find that DOCK1 levels determine the anti-tumor effects of met-formin and that DOCK1 is a synthetic lethal target of metformin in HCC.Mechanistically,metformin promotes DOCK1 phosphorylation,which activates RAC1 to facilitate cell survival,leading to metformin resistance.The DOCK1-selective inhibitor,TBOPP,potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids,and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models.Notably,metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression.This study shows that metformin effective-ness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for met-formin-resistant HCC patients.
文摘细胞质分裂付出蛋白1(dedicator of cytokinesis 1,DOCK1)作为Rho GTP酶家族的关键上游分子,在细胞迁移过程中发挥关键性的作用。细胞表面受体与配体结合后,通过一系列衔接蛋白招募并活化DOCK1蛋白,进而促进细胞生长和迁移等生物学过程。活化的DOCK1通过激活Rac1调节下游的肌动蛋白组装,从而影响细胞迁移、粘附和存活。DOCK1在癌细胞迁移和侵袭中的作用越来越受到重视。DOCK1在肺癌、膀胱癌、卵巢癌、急性髓系白血病等多种肿瘤中的过度表达与其预后差相关。DOCK1在肿瘤细胞的迁移、肿瘤血管生成以及肿瘤耐药方面发挥重要作用。提示DOCK1是一个治疗癌转移的可能靶点。
基金Birla Institute of Technology for providing financial support as a prestigious Institute fellowship
文摘A series of 2-（arylmethylidene）-2,3-dihydro-1-benzofuran-3-one derivatives（aurones, 1–20） were synthesized and screened for their inhibitory activity against h MAO. Seventeen compounds（1–5, 7–17,19） were found to be selective towards h MAO-B, while two were non-selective（6 and 20） and one（18）selective towards h MAO-A. Compound 17（Ki = 0.10 0.01 mmol/L） was found to be equally potent and selective towards h MAO-B, when compared with the standard drug Selegiline（Ki = 0.12 0.01 mmol/L）.Nature and position of substitution in aryl ring at 2nd position of benzofuranone influences h MAO-B inhibitory potency, while their structural bulkiness influences selectivity between h MAO-A and h MAO-B.Molecular docking simulation was also carried out to understand the interaction of inhibitor with the enzyme at molecular level, and we found the docking results were in good agreement with the experimental values. Comparison of the activity profile of the aurones with their corresponding flavones reported earlier by our group revealed that there exists no difference in potency as well as selectivity.
基金Hibah PUPT BOPTN Ditjen Dikti 2015 No.0528/UN2.R12/HKP.05.00/2015,for supporting this research
文摘Highly Pathogenic Avian Influenza（HPAI） H5N1 has attracted much attention as a potential pandemic virus in humans, which makes death inevitable in humans. Neuraminidase（NA） has an important role in viral replication. Thus, it is an attractive target when designing anti-influenza virus drug. However, evolving viruses cause some anti-viral drugs to be ineffective, as they show resistance to them. Selection of peptides as drug candidates is important for the peptide-receptor activity and good selectivity. Cyclic bonds in the peptide ligand design aim to improve the stability of the system and remove the obstacles in drug metabolism. The design is based on the polarity of the ligand and amino acid residues in the active site of NA. The results are 4200 cyclic pentapeptides as potential lead compounds. Docking simulations were conducted using MOE 2008.10 and were screened based on the value of the binding energy（？Gbinding）. ADME-Tox prediction assay was conducted on the selected ligands.Intra- and inter-molecular interactions, as well as changes in the form of bonds, were tested by molecular dynamics simulations at temperatures of 310 K and 312 K. The results of the docking simulations and toxicity prediction assay show that there are two ligands that have a residual interaction with the target protein： CLDRC and CIWRC. These two ligands have ？Gbindingvalues of –40.5854 and –39.9721 kcal/mol（1 kcal/mol = 4.18 k J/mol）. These ligands are prone to be mutagenic and carcinogenic, and they have a good oral bioavailability. The results show that the molecular dynamics of both ligand CLDRC and CIWRC are more feasible at the temperature of 312 K. At the end,both CIWRC and CLDRC ligands can be used as the drug candidates against H5N1 virus.
