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  • 1
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    Target-oriented and diversity-oriented organic synthesis in drug discovery (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-03-17
    Description: Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schreiber, S L -- New York, N.Y. -- Science. 2000 Mar 17;287(5460):1964-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. sls@slsiris.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10720315" target="_blank"〉PubMed〈/a〉
    Keywords: *Chemistry, Pharmaceutical ; *Drug Design ; Drug Evaluation, Preclinical ; Models, Chemical ; Organic Chemicals/*chemical synthesis/chemistry/metabolism/pharmacology ; Pharmaceutical Preparations/*chemical synthesis/chemistry/metabolism ; Protein Binding ; Proteins/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Printing proteins as microarrays for high-throughput function determination (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-09-08
    Description: Systematic efforts are currently under way to construct defined sets of cloned genes for high-throughput expression and purification of recombinant proteins. To facilitate subsequent studies of protein function, we have developed miniaturized assays that accommodate extremely low sample volumes and enable the rapid, simultaneous processing of thousands of proteins. A high-precision robot designed to manufacture complementary DNA microarrays was used to spot proteins onto chemically derivatized glass slides at extremely high spatial densities. The proteins attached covalently to the slide surface yet retained their ability to interact specifically with other proteins, or with small molecules, in solution. Three applications for protein microarrays were demonstrated: screening for protein-protein interactions, identifying the substrates of protein kinases, and identifying the protein targets of small molecules.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉MacBeath, G -- Schreiber, S L -- New York, N.Y. -- Science. 2000 Sep 8;289(5485):1760-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genomics Research, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA. gavin_macbeath@harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10976071" target="_blank"〉PubMed〈/a〉
    Keywords: Biochemistry/*methods ; Biotin/metabolism ; Digoxigenin/metabolism ; Fluorescence ; Fluorescent Dyes ; Ligands ; *Molecular Probe Techniques ; Phosphorylation ; Piperazines/pharmacology ; *Protein Binding ; Protein Folding ; Protein Kinases/*metabolism ; Proteins/*chemistry/*metabolism ; Robotics ; Serum Albumin, Bovine
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-11-05
    Description: Small molecules that perturb specific protein functions are valuable tools for dissecting complex processes in mammalian cells. A combination of two phenotype-based screens, one based on a specific posttranslational modification, the other visualizing microtubules and chromatin, was used to identify compounds that affect mitosis. One compound, here named monastrol, arrested mammalian cells in mitosis with monopolar spindles. In vitro, monastrol specifically inhibited the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. All previously known small molecules that specifically affect the mitotic machinery target tubulin. Monastrol will therefore be a particularly useful tool for studying mitotic mechanisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mayer, T U -- Kapoor, T M -- Haggarty, S J -- King, R W -- Schreiber, S L -- Mitchison, T J -- CA78048/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1999 Oct 29;286(5441):971-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, and Institute of Chemistry and Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Thomas_Mayer@hms.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10542155" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/drug effects ; Animals ; Cattle ; Cell Line ; Cytoskeleton/drug effects ; Golgi Apparatus/drug effects ; Kinesin/*drug effects ; Microtubules/drug effects ; Mitosis/*drug effects ; Molecular Motor Proteins/drug effects ; Phenotype ; Phosphoproteins/metabolism ; Protein Processing, Post-Translational ; Pyrimidines/*pharmacology ; RNA-Binding Proteins/metabolism ; Spindle Apparatus/*drug effects ; Thiones/*pharmacology ; Tumor Cells, Cultured ; Xenopus ; *Xenopus Proteins
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-14
    Description: Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christofk, Heather R -- Vander Heiden, Matthew G -- Harris, Marian H -- Ramanathan, Arvind -- Gerszten, Robert E -- Wei, Ru -- Fleming, Mark D -- Schreiber, Stuart L -- Cantley, Lewis C -- R01 GM056203/GM/NIGMS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 13;452(7184):230-3. doi: 10.1038/nature06734.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337823" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Animals ; Cell Line, Tumor ; Cell Proliferation ; Fructosediphosphates/metabolism ; Gene Expression Regulation, Neoplastic ; Glycolysis ; Humans ; Lactic Acid/metabolism ; Lung Neoplasms/genetics/metabolism/pathology ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms/enzymology/genetics/*metabolism/*pathology ; Oxidative Phosphorylation ; Oxygen Consumption ; Pyruvate Kinase/*genetics/*metabolism ; Pyruvic Acid/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 5
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    Organic chemistry: Molecular diversity by design (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-01-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schreiber, Stuart L -- England -- Nature. 2009 Jan 8;457(7226):153-4. doi: 10.1038/457153a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19129834" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Products/*chemical synthesis/*chemistry ; *Drug Design ; Drug Evaluation, Preclinical/*methods ; Drug Industry/methods ; Humans
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 6
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    Solution structure of FKBP, a rotamase enzyme and receptor for FK506 and rapamycin (1991)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1991-05-10
    Description: Immunophilins, when complexed to immunosuppressive ligands, appear to inhibit signal transduction pathways that result in exocytosis and transcription. The solution structure of one of these, the human FK506 and rapamycin binding protein (FKBP), has been determined by nuclear magnetic resonance (NMR). FKBP has a previously unobserved antiparallel beta-sheet folding topology that results in a novel loop crossing and produces a large cavity lined by a conserved array of aromatic residues; this cavity serves as the rotamase active site and drug-binding pocket. There are other significant structural features (such as a protruding positively charged loop and an apparently flexible loop) that may be involved in the biological activity of FKBP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Michnick, S W -- Rosen, M K -- Wandless, T J -- Karplus, M -- Schreiber, S L -- GM-30804/GM/NIGMS NIH HHS/ -- GM-38627/GM/NIGMS NIH HHS/ -- I-S10-RR04870/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 1991 May 10;252(5007):836-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Harvard University, Cambridge, MA 02138.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1709301" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/metabolism ; Binding Sites ; Carrier Proteins/*ultrastructure ; Crystallography ; Humans ; Immunosuppressive Agents/metabolism ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Polyenes/metabolism ; Sirolimus ; Tacrolimus ; Tacrolimus Binding Proteins
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex (1991)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1991-05-10
    Description: The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography. The conformation of the protein changes little upon complexation, but the conformation of FK506 is markedly different in the bound and unbound forms. The drug's association with the protein involves five hydrogen bonds, a hydrophobic binding pocket lined with conserved aromatic residues, and an unusual carbonyl binding pocket. The nature of this complex has implications for the mechanism of rotamase catalysis and for the biological actions of FK506 and rapamycin.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Duyne, G D -- Standaert, R F -- Karplus, P A -- Schreiber, S L -- Clardy, J -- CA-24487/CA/NCI NIH HHS/ -- GM-38627/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1991 May 10;252(5007):839-42.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1709302" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/*metabolism ; Binding Sites ; Carrier Proteins/*ultrastructure ; Humans ; *Immunosuppressive Agents ; Molecular Structure ; Tacrolimus ; Tacrolimus Binding Proteins ; X-Ray Diffraction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    Prevention of HIV-1 infection and preservation of CD4 function by the binding of CPFs to gp120 (1990)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1990-07-20
    Description: Infection by human immunodeficiency virus type-1 (HIV-1) is initiated when its envelope protein, gp120, binds to its receptor, the cell surface glycoprotein CD4. Small molecules, termed N-carbomethoxycarbonyl-prolyl-phenylalanyl benzyl esters (CPFs), blocked this binding. CPFs interacted with gp120 and did not interfere with the binding of CD4 to class II major histocompatibility complex molecules. One CPF isomer, CPF(DD), preserved CD4-dependent T cell function while inhibiting HIV-1 infection of H9 tumor cells and human T cells. Although the production of viral proteins in infected T cells is unaltered by CPF(DD), this compound prevents the spread of infection in an in vitro model system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Finberg, R W -- Diamond, D C -- Mitchell, D B -- Rosenstein, Y -- Soman, G -- Norman, T C -- Schreiber, S L -- Burakoff, S J -- New York, N.Y. -- Science. 1990 Jul 20;249(4966):287-91.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2115689" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD4/*immunology ; Antiviral Agents/*pharmacology ; Benzyl Compounds/pharmacology ; Cell Line ; Genes, MHC Class II ; HIV Envelope Protein gp120/*immunology ; HIV-1/drug effects/immunology/*physiology ; Humans ; Kinetics ; T-Lymphocytes/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    Chemistry and biology of the immunophilins and their immunosuppressive ligands (1991)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1991-01-18
    Description: Cyclosporin A, FK506, and rapamycin are inhibitors of specific signal transduction pathways that lead to T lymphocyte activation. These immunosuppressive agents bind with high affinity to cytoplasmic receptors termed immunophilins (immunosuppressant binding proteins). Studies in this area have focused on the structural basis for the molecular recognition of immunosuppressants by immunophilins and the biological consequences of their interactions. Defining the biological roles of this emerging family of receptors and their ligands may illuminate the process of protein trafficking in cells and the mechanisms of signal transmission through the cytoplasm.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schreiber, S L -- GM-38627/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1991 Jan 18;251(4991):283-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University, Cambridge, MA 02138.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1702904" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Isomerases/*physiology ; Animals ; Anti-Bacterial Agents/metabolism/*pharmacology ; Carrier Proteins/*physiology ; Cyclosporins/metabolism/*pharmacology ; Humans ; Immunosuppressive Agents/metabolism/*pharmacology ; Isomerases/antagonists & inhibitors/*physiology ; Ligands ; *Lymphocyte Activation ; Peptidylprolyl Isomerase ; Polyenes/metabolism/pharmacology ; Receptors, Immunologic/*physiology ; Sirolimus ; T-Lymphocytes/*physiology ; Tacrolimus ; Tacrolimus Binding Proteins
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Solution structure of the SH3 domain of Src and identification of its ligand-binding site (1992)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1992-12-04
    Description: The Src homology 3 (SH3) region is a protein domain of 55 to 75 amino acids found in many cytoplasmic proteins, including those that participate in signal transduction pathways. The solution structure of the SH3 domain of the tyrosine kinase Src was determined by multidimensional nuclear magnetic resonance methods. The molecule is composed of two short three-stranded anti-parallel beta sheets packed together at approximately right angles. Studies of the SH3 domain bound to proline-rich peptide ligands revealed a hydrophobic binding site on the surface of the protein that is lined with the side chains of conserved aromatic amino acids.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, H -- Rosen, M K -- Shin, T B -- Seidel-Dugan, C -- Brugge, J S -- Schreiber, S L -- 1-S10-RR04870/RR/NCRR NIH HHS/ -- CA27951/CA/NCI NIH HHS/ -- GM44993/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1992 Dec 4;258(5088):1665-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Harvard University, Cambridge, MA 02138.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1280858" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Cloning, Molecular ; Escherichia coli/genetics ; Glutathione Transferase/chemistry/genetics/isolation & purification ; Ligands ; Magnetic Resonance Spectroscopy ; Molecular Sequence Data ; Neurons/physiology ; Protein Conformation ; *Protein Structure, Secondary ; Protein-Tyrosine Kinases/*genetics ; Proto-Oncogene Proteins pp60(c-src)/*chemistry ; Recombinant Fusion Proteins/chemistry/isolation & purification ; Solutions ; X-Ray Diffraction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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