- Strategy and validation of a structure-based method for the discovery of selective inhibitors of PAK isoforms and the evaluation of their anti-cancer activity
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p21 activated kinase 4 (PAK4), which belongs to the serine/threonine (Ser/Thr) protein kinase family, is a representative member of the PAK family and plays a significant role in multiple processes associated with cancer development. In this study, structure-based virtual screening was performed to discover novel and selective small molecule scaffolds, and a 6-hydroxy-2-mercapto-3-phenylpyrimidin-4(3H)-one-based compound (SPU-106, 14No.) was identified as an effective PAK4 inhibitor. By combining both a molecular docking study and molecular dynamics (MD) simulation strategies, the binding mode was determined in the PAK4 site. The SPU-106 compound could efficiently and selectively bind to the PAK4 kinase domain at an IC50 of 21.36 μM according to the kinase analysis. The designed molecular probe demonstrated that SPU-106 binds to the kinase domain in the C-terminus of PAK4. Further investigation revealed that the SPU-106 had a strong inhibitory effect on the invasion of SGC7901 cells but without any cytotoxicity. The western blot analysis indicated that the compound potently inhibited the PAK4/LIMK1/cofilin and PAK4/SCG10 signaling pathways. Thus, our work shows the successful application of computational strategies for the discovery of selective hits, and SPU-106 may be an effective PAK4 inhibitor for further development as an antitumor agent.
- Song, Pei-Lu,Wang, Gang,Su, Yuan,Wang, Han-Xun,Wang, Jian,Li, Feng,Cheng, Mao-Sheng
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- Tumor targeting metal complex, synthetic method and application
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The invention discloses a tumor targeting metal complex, a synthetic method and application. The synthetic method comprises the steps of connecting a ligand with a substituent group and a targeting molecule, complexing the ligand and metal ions, and synthesizing to obtain the tumor targeting metal complex, wherein the ligand is one of a phenanthroline derivative, a dipyridyl derivative, a benzimidazole derivative, a phenyl-pyridine derivative and a thiophene-pyridine derivative; the targeting molecule is one of biotin, folic acid, integrin, transferrin, cell-penetrating peptide, octa-poly-L-arginine, MUC-1 attached membrane protein, galactosamine, neovascular targeting peptide and a granulocyte-macrophage colony-stimulating factor; the metal ions are ruthenium, osmium, rhodium or iridium ions. The complex obtained by the method provided by the invention can be selectively absorbed by tumor cells, and induces apoptosis of the tumor cells. In a nude mouse tumor-bearing model, the tumor targeting metal complex can image and treat tumors, and the toxicity of organs and tissues is reduced.
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- Biomolecule-compatible, highly branched polymer and biomolecular-recognition surface
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A biomolecule-compatible highly branched polymer obtained by polymerizing a monomer having an alkylene oxide and two or more radically polymerizable double bonds in a molecule in presence of a polymerization initiator in 5 mol % or more and 200 mol % or less relative to the moles of monomer, wherein molecular terminals of biomolecule-compatible highly branched polymer have one biomolecular site of at least one pair from the group of combination pairs of biotin and avidin, an antigen and antibody, polynucleotide and polynucleotide having complementary base sequence thereof, cDNA and mRNA, enzyme and substrate, an enzyme and product, an enzyme and competitive inhibitor, an enzyme (binding site) and coenzyme, an enzyme (binding site) and triazine dye, protease and protease inhibitor, Fc site and protein A, Fc site and protein G, lectin and sugar, hormone receptor and hormone, DNA and DNA binding protein, heparin and fibronectin, and heparin and laminin.
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Page/Page column 15
(2016/04/05)
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- Photocleavable ligands for protein decoration of DNA nanostructures
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This work describes the synthesis of amino-reactive, photocleavable hapten-modifiers and their application as affinity tags for DNA nanostructures. In particular, N-hydroxysuccinimide-activated linkers containing an α-methyl-nitroveratryl-butyric acid group and carboxyfluorescein or biotin were synthesized and coupled to alkyl-amino-modified DNA oligonucleotides. The resulting conjugates were then incorporated into DNA origami nanostructures. As demonstrated by electrophoresis and AFM imaging, the functionalized nanostructures were capable to bind cognate proteins which could then be cleaved-off by irradiation. Owing to its modularity, this approach to control protein binding should be useful for a wide variety of functional DNA nanostructures.
- Brglez, Josipa,Ahmed, Ishtiaq,Niemeyer, Christof M.
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supporting information
p. 5102 - 5104
(2015/05/13)
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- Analyte detection utilizing polynucleotide sequences, composition, process and kit
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A method of detecting in a sample an analyte (A) having a molecularly recognizable portion thereon, which comprises: providing (B) a molecular bridging entity having thereon: (i) a portion capable of recognizing the molecularly recognizable portion on the analyte; and (ii) a portion comprising a polynucleotide sequence; and (C) a signalling entity having thereon: (i) a polynucleotide portion capable of annealing to the polynucleotide portion of the bridging entity, thereby to form a stable polynucleotide hybrid, and (ii) a signal generating portion; forming a complex comprising: (1) the analyte (A) complexed through its molecularly recognizable portion to (2) the recognizing portion of the entity (B); the entity (B) being complexed through the polynucleotide portion thereon to (3) the polynucleotide portion of the signalling entity; and detecting a signal by means of the signal generating portion present in the complex.
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- Active/inactive dual-probe system for selective photoaffinity labeling of small molecule-binding proteins
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Two are better than one: A new approach to selective photoaffinity labeling is described in which a bioactive probe is used in combination with its inactive analog as a scavenger of nonspecific proteins. Copyright
- Sakurai, Kaori,Tawa, Masaki,Okada, Ayumi,Yamada, Rika,Sato, Noriyuki,Inahara, Masahiro,Inoue, Maia
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supporting information; experimental part
p. 1567 - 1571
(2012/09/22)
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- A surface plasmon enhanced fluorescence sensor platform
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Surface-immobilised and fluorophore-labelled boronic acids were prepared and used for the specific detection of quencher-labelled diols. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009.
- Elfeky, Souad A.,D'Hooge, Franois,Poncel, Lora,Chen, Wenbo,Perera, Semali P.,Van Den Elsen, Jean M. H.,James, Tony D.,Jenkins, A. Toby A.,Cameron, Petra J.,Fossey, John S.
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experimental part
p. 1466 - 1469
(2009/10/30)
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- Synthesis and structural characterization of carboxyethylpyrrole-modified proteins: Mediators of age-related macular degeneration
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Protein modifications in which the σ-amino group of lysyl residues is incorporated into a 2-(oωcarboxyethyl)pyrrole (CEP) are mediators of age-related macular degeneration (AMD). They promote both angiogenesis into the retina ('wet AMD') and geographic re
- Lu, Liang,Gu, Xiaorong,Hong, Li,Laird, James,Jaffe, Keeve,Choi, Jaewoo,Crabb, John,Salomon, Robert G.
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experimental part
p. 7548 - 7561
(2011/02/23)
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- Biotin sulfone as a new tool for synthetic oligosaccharide immobilization: Application to multiple analysis profiling and surface plasmonic analysis of anti-Candida albicans antibody reactivity against α and β (1→2) oligomannosides
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As a part of our glycoantigen synthetic program for diagnosis and basic analysis of yeast-related pathogenic mechanisms, a library of 1→2 oligomannosides suitable for immunoanalysis was prepared. The use of biotin sulfone, an oxidized form of biotin, offe
- Collot, Mayeul,Sendid, Boualem,Fievez, Aurélie,Savaux, Camille,Standaert-Vitse, Annie,Tabouret, Marc,Drucbert, Anne Sophie,Danzé, Pierre Marie,Poulain, Daniel,Mallet, Jean-Maurice
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experimental part
p. 6201 - 6210
(2009/10/17)
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- A new biotin derivative-DOTA conjugate as a candidate for pretargeted diagnosis and therapy of tumors
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The synthesis of a new biotin derivative, the (CO) reduced N-aminohexyl biotinamido derivative, designed to be serum biotinidase resistant, and its conjugation to the chelator DOTA through an amide bond at one of the four carboxymethyl chains are described. The 90Y-labeled conjugate was able to bind avidin at different Av/conjugate molar ratios with good results. The preclinical results indicate that this new biotin-DOTA conjugate is a good candidate for pretargeted diagnosis and therapy of tumors.
- Sabatino, Giuseppina,Chinol, Marco,Paganelli, Giovanni,Papi, Stefano,Chelli, Mario,Leone, Giuseppe,Papini, Anna Maria,De Luca, Angelo,Ginanneschi, Mauro
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p. 3170 - 3173
(2007/10/03)
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