title: Novel PTP1B inhibitors identified by DNA display of fragment pairs.
abstract: DNA display of PNA-encoded libraries was used to pair fragments containing different phosphotyrosine surrogates with diverse triazoles. Microarray-based screening of the combinatorially paired fragment sets (62,500 combinations) against a prototypical phosphatase, PTP1B, was used to identify the fittest fragments. A focused library (10,000 members) covalently pairing identified fragments with linkers of different length and geometry was synthesized. Screening of the focused library against PTP1B and closely related TCPTP revealed orthogonal inhibitors. The selectivity of the identified inhibitors for PTP1B versus TCPT was confirmed by enzymatic inhibition assay.
authors.affiliation: Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Switzerland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Barluenga
authors.affiliation: Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zambaldo
authors.affiliation: Current affiliation: Departement of Life and Health Science University of Nicosia, Cyprus.
authors.forename: Heraklidia A
authors.initials: HA
authors.lastname: Ioannidou
authors.affiliation: Current affiliation: Lonza AG, Visp, Switzerland.
authors.forename: Mihai
authors.initials: M
authors.lastname: Ciobanu
authors.affiliation: Current affiliation: PerkinElmer SAS, Villebon-sur-Yvette, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morieux
authors.affiliation: Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Switzerland.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Daguer
authors.affiliation: Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Winssinger
mesh_terms: D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D046228:Microarray Analysis; D020135:Peptide Nucleic Acids / Q000737:chemistry; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020135:Peptide Nucleic Acids; D054852:Small Molecule Libraries; D004247:DNA; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: DNA-encoded library; Fragment based drug discovery; PTP1B; Peptide nucleic acid (PNA)