PTP1B as a drug target: recent developments in PTP1B inhibitor discovery.

Protein tyrosine phosphatase 1B (PTP1B) is an effective target for the treatment of both type 2 diabetes and obesity; however, targeting PTP1B for drug discovery is challenging because of the highly conserved and positively charged active-site pocket. Tremendous progress has been made in the development of potent and selective PTP1B inhibitors that engage both the active site and no catalytic sites. Several strategies are being pursued to improve the pharmacological properties of PTP1B inhibitors. These new developments suggest that it is feasible to acquire PTP1B-based, small-molecule therapeutics with the requisite potency and selectivity. Future efforts will probably transform the potent and selective PTP1B inhibitors into orally available drugs with desirable physicochemical properties and in vivo efficacies.

[1]  John D. Minna,et al.  Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia , 2004, Cancer Research.

[2]  P. Almgren,et al.  A variation in 3' UTR of hPTP1B increases specific gene expression and associates with insulin resistance. , 2002, American journal of human genetics.

[3]  D. Lawrence,et al.  Acquisition of a Specific and Potent PTP1B Inhibitor from a Novel Combinatorial Library and Screening Procedure* , 2001, The Journal of Biological Chemistry.

[4]  Matthew L. Thomas,et al.  Evidence that the leukocyte-common antigen is required for antigen-induced T lymphocyte proliferation , 1989, Cell.

[5]  Zhon-Yin Zhang,et al.  Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug. , 2007, Journal of medicinal chemistry.

[6]  J. Licht,et al.  Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia , 2003, Nature Genetics.

[7]  Wang Shen,et al.  Allosteric inhibition of protein tyrosine phosphatase 1B , 2004, Nature Structural &Molecular Biology.

[8]  Young-Bum Kim,et al.  PTP1B regulates leptin signal transduction in vivo. , 2002, Developmental cell.

[9]  T. Mustelin,et al.  SHP1 expression in bone marrow biopsies of myelodysplastic syndrome patients: a new prognostic factor , 2005, British journal of haematology.

[10]  J. Melo,et al.  Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[11]  Meredith Williams,et al.  Synthesis and biological activity of a novel class of pyridazine analogues as non-competitive reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). , 2002, Bioorganic & medicinal chemistry.

[12]  D. Joseph-McCarthy,et al.  Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors: capturing interactions with Asp48. , 2006, Bioorganic & medicinal chemistry letters.

[13]  J. Waring,et al.  PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Zhon-Yin Zhang,et al.  Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. , 2002, Annual review of pharmacology and toxicology.

[15]  Z. Zhang,et al.  Protein tyrosine phosphatases: prospects for therapeutics. , 2001, Current opinion in chemical biology.

[16]  B. Neel,et al.  Neuronal PTP1B regulates body weight, adiposity and leptin action , 2006, Nature Medicine.

[17]  A. Nebreda,et al.  Protein kinases and phosphatases as therapeutic targets in cancer , 2006, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[18]  Daniel A Erlanson,et al.  Discovery of a new phosphotyrosine mimetic for PTP1B using breakaway tethering. , 2003, Journal of the American Chemical Society.

[19]  P. Hajduk,et al.  Identification of a monoacid-based, cell permeable, selective inhibitor of protein tyrosine phosphatase 1B. , 2003, Bioorganic & Medicinal Chemistry Letters.

[20]  T. Hunter,et al.  Signaling—2000 and Beyond , 2000, Cell.

[21]  A. Moretto,et al.  Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors. , 2006, Bioorganic & medicinal chemistry.

[22]  C. Bayly,et al.  The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. , 2003, Biochemistry.

[23]  C. Desponts,et al.  Conformation-assisted Inhibition of Protein-tyrosine Phosphatase-1B Elicits Inhibitor Selectivity over T-cell Protein-tyrosine Phosphatase* , 2006, Journal of Biological Chemistry.

[24]  B. Zinman,et al.  A single nucleotide polymorphism in protein tyrosine phosphatase PTP-1B is associated with protection from diabetes or impaired glucose tolerance in Oji-Cree. , 2002, The Journal of clinical endocrinology and metabolism.

[25]  Jon Read,et al.  Structure-based design of protein tyrosine phosphatase-1B inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[26]  J. Chernoff,et al.  Protein-Tyrosine Phosphatase 1B Complexes with the Insulin Receptor in Vivo and Is Tyrosine-phosphorylated in the Presence of Insulin* , 1997, The Journal of Biological Chemistry.

[27]  Q. Dang.  Organophosphonic acids as drug candidates , 2006 .

[28]  M. Bower,et al.  Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: synthesis and structure-activity relationships of a peptide scaffold. , 2006, Bioorganic & medicinal chemistry.

[29]  T. Hunter,et al.  The Croonian Lecture 1997. The phosphorylation of proteins on tyrosine: its role in cell growth and disease. , 1998, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[30]  Ole Hvilsted Olsen,et al.  Structure-based Design of a Low Molecular Weight, Nonphosphorus, Nonpeptide, and Highly Selective Inhibitor of Protein-tyrosine Phosphatase 1B* , 2000, The Journal of Biological Chemistry.

[31]  X Y Wang,et al.  Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action. , 2001, Biochemistry.

[32]  M. Kasuga,et al.  Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. , 1994, Molecular and cellular biology.

[33]  R. Geahlen,et al.  Design and synthesis of phosphotyrosine peptidomimetic prodrugs. , 2006, Journal of medicinal chemistry.

[34]  N. Tonks.  PTP1B: From the sidelines to the front lines! , 2003, FEBS letters.

[35]  Rob Hooft van Huijsduijnen,et al.  Selecting protein tyrosine phosphatases as drug targets. , 2002, Drug Discovery Today.

[36]  Gang Liu,et al.  Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. , 2003, Journal of medicinal chemistry.

[37]  Jerrold M. Olefsky,et al.  Protein-tyrosine Phosphatase 1B Is a Negative Regulator of Insulin- and Insulin-like Growth Factor-I-stimulated Signaling* , 1996, The Journal of Biological Chemistry.

[38]  D. Ogg,et al.  Investigation of potential bioisosteric replacements for the carboxyl groups of peptidomimetic inhibitors of protein tyrosine phosphatase 1B: identification of a tetrazole-containing inhibitor with cellular activity. , 2002, Journal of medicinal chemistry.

[39]  D. Beier,et al.  Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene , 1993, Cell.

[40]  Joanna M. Sasin,et al.  Protein Tyrosine Phosphatases in the Human Genome , 2004, Cell.

[41]  D. Lawrence,et al.  Cellular effects of small molecule PTP1B inhibitors on insulin signaling. , 2003, Biochemistry.

[42]  Gang Liu,et al.  Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. , 2003, Journal of the American Chemical Society.

[43]  Toshiyuki Fukada,et al.  A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[44]  M. J. Newman,et al.  Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B. , 2002, Journal of medicinal chemistry.

[45]  Michael A. Patton,et al.  Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome , 2001, Nature Genetics.

[46]  S. Arkinstall,et al.  Identification of Tyrosine Phosphatases That Dephosphorylate the Insulin Receptor , 2000, The Journal of Biological Chemistry.

[47]  Gang Liu,et al.  Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands. , 2003, Journal of medicinal chemistry.

[48]  D S Lawrence,et al.  Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[49]  M. White,et al.  Tyrosine Dephosphorylation and Deactivation of Insulin Receptor Substrate-1 by Protein-tyrosine Phosphatase 1B , 2000, The Journal of Biological Chemistry.

[50]  A. Fedorov,et al.  Crystal Structure of PTP1B Complexed with a Potent and Selective Bidentate Inhibitor* , 2003, The Journal of Biological Chemistry.

[51]  D. Ogg,et al.  Synthesis and biological activity of a novel class of small molecular weight peptidomimetic competitive inhibitors of protein tyrosine phosphatase 1B. , 2002, Journal of medicinal chemistry.

[52]  B. Kennedy,et al.  Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. , 2002, Developmental cell.

[53]  Zhon-Yin Zhang,et al.  PTP1B inhibitors as potential therapeutics in the treatment of Type 2 diabetes and obesity , 2003, Expert opinion on investigational drugs.

[54]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[55]  Young-Bum Kim,et al.  Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice , 2000, Molecular and Cellular Biology.

[56]  Thomas R Downs,et al.  1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[57]  C. Bayly,et al.  Structure based design of a series of potent and selective non peptidic PTP-1B inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[58]  Karl Blom,et al.  Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics. , 2005, Journal of medicinal chemistry.

[59]  E. Asante-Appiah,et al.  The development of potent non-peptidic PTP-1B inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[60]  M. R. Calera,et al.  Dynamics of Protein-tyrosine Phosphatases in Rat Adipocytes* , 2000, The Journal of Biological Chemistry.

[61]  J. Chernoff,et al.  Down-regulation of Insulin Signaling by Protein-tyrosine Phosphatase 1B Is Mediated by an N-terminal Binding Region* , 2000, The Journal of Biological Chemistry.

[62]  J. Meyerovitch,et al.  Osmotic Loading of Neutralizing Antibodies Demonstrates a Role for Protein-tyrosine Phosphatase 1B in Negative Regulation of the Insulin Action Pathway (*) , 1995, The Journal of Biological Chemistry.

[63]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[64]  M. Bower,et al.  Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic. , 2006, Journal of medicinal chemistry.

[65]  Christopher W Murray,et al.  Fragment-based lead discovery using X-ray crystallography. , 2005, Journal of medicinal chemistry.

[66]  J. Berman,et al.  Gastrointestinal stromal tumor workshop. , 2001, Human pathology.

[67]  J. Kusari,et al.  Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction , 1998, Molecular and Cellular Biochemistry.

[68]  M. Wasik,et al.  STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  A. Bardelli,et al.  Genetic analysis of the kinome and phosphatome in cancer , 2005, Cellular and Molecular Life Sciences CMLS.

[70]  H. Waldmann,et al.  Inhibitors of protein tyrosine phosphatases: next-generation drugs? , 2005, Angewandte Chemie.

[71]  D. V. Von Hoff,et al.  PRL phosphatases as potential molecular targets in cancer , 2005, Molecular Cancer Therapeutics.

[72]  Giovanni Parmigiani,et al.  Mutational Analysis of the Tyrosine Phosphatome in Colorectal Cancers , 2004, Science.

[73]  N. Perrimon,et al.  corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso , 1992, Cell.

[74]  D. Lawrence,et al.  Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. , 2007, Endocrinology.