Cold Spring Harbor Laboratory

Depymed, Inc.

The Penn State Research Foundation

Nicholas K Tonks

Navasona Krishnan

Arne Ostman

Andreas Grill

Howard Sard

Andrew J Flint

Stephen J Benkovic

Chun Yu Liu

Helena L Palka-Hamblin

Chunliang Liu

Aftabul Haque

Compounds of formula: are described herein. The compounds selectively complex copper and are therefore useful both abiotically for measuring and detecting small amounts of copper and, in biological systems, for treating diseases associated with inappropriate copper levels, such as Wilson's disease and gastric cancer.

(Pyridinylmethyl)butanediamine derivatives that chelate copper

Provided is a method of forming a copper-containing complex, including contacting a sample containing copper with a compound of Formula I: wherein R is —OH or —O—CH. Also provided is a method of inhibiting enzymatic activity of a kinase in a sample, including contacting the sample with a compound of Formula I. Further provided is a method of administering to a subject a pharmaceutical composition including a compound of Formula I optionally complexed with copper. Also provided is a pharmaceutical composition including copper complexed with a compound of Formula I.

Method and compositions for forming a copper-containing complex and uses thereof

The present invention relates to agents and methods for treating autism spectrum disorders, such as Rett Syndrome.

Treatment of Rett syndrome

Provided is a method of forming a copper-containing complex, including contacting a sample containing copper with a compound of Formula I:  wherein R is &#x2014;OH or &#x2014;O&#x2014;CH3. Also provided is a method of inhibiting enzymatic activity of a kinase in a sample, including contacting the sample with a compound of Formula I. Further provided is a method of administering to a subject a pharmaceutical composition including a compound of Formula I optionally complexed with copper. Also provided is a pharmaceutical composition including copper complexed with a compound of Formula I.

A method is disclosed for altering the redox equilibrium of a transmembrane receptor-like protein tyrosine phosphatase (RPTP), particularly a type IIa RPTP, by chemically modulating the activity through contact of such an enzyme with a diaryl boron compound that preferentially reacts with an RPTP in an oxidized state (CyS-OH). This redox modulation is most readily observed and put to use by assaying the inhibition of the phosphatase activity of the RPTP. Such an assay can be carried out on an enzyme in vitro or by contacting the enzyme in a living organism (in vivo). A useful diaryl boron compound corresponds in structure to Formula I in which Ar-1, Ar-2, R, R, Rand Rare defined within. A pharmaceutical composition containing a useful diaryl boron compound is also disclosed, as are particularly preferred diaryl boron compounds.

Boron-containing small molecules for inhibiting activity of a receptor-like protein tyrosine phosphatase

Described herein are agents, including antibodies, antibody fragments, polypeptides and organic small molecules, that bind reversibly inactive PTP1B (designated herein in the alternative as PTP1B-SN or PTP1B-OX) and stabilize it (stabilize PTP1B-OX) in such a manner that they inhibit reactivation of reversibly oxidized, inactive PTP1B by reduction (by reducing agent) and have no substantial direct inhibitory effect on phosphatase activity/PTP1B activity (for example, as detectable in assays in vitro).

PTP1B inhibitors

Proteins are identified from human breast tumor cell lines (MDA-MB-231, T-47D and T-47D/Met) that interact specifically with the substrate-trapping mutant form of Density Enhanced Phosphatase-1 (DEP-1). These proteins include the functional component p120 catenin (p120), the adaptor protein Gab 1, and the HGF/SF receptor Met. The invention relates to isolated complexes comprising DEP-1 polypeptides in specific association with Met, Gab 1, or p120, identified herein as DEP-1 substrate polypeptides. Screening assays for agents that alter DEP-1 interaction with DEP-1 substrate polypeptides are also disclosed, as are methods for altering biological signals in cells that are transduced via DEP-1 pathways.

DEP-1 receptor protein tyrosine phosphatase interacting proteins and related methods

Novel Type III density enhanced protein tyrosine phosphatases are disclosed and exemplified by human DEP-1 enzyme. Polynucleotides encoding huDEP-1 are disclosed, along with methods and materials for production of the same by recombinant procedures. Binding molecules specific for DEP-1 are also disclosed as useful for modulating the biological activities of DEP-1.

Density enhanced protein tyrosine phosphatases

An antibody is provided that is specific for a PTPH1 protein, a phosphatase that dephosphorylates phosphotyrosine residues in phosphoproteins having tyrosyl residues that are phosphorylated by tyrosine kinases. The PTPH1 protein localizes to focal adhesions, a major site of action for oncogenic protein tyrosine kinases. PTPH1 overexpression may counter the effects of oncogenic protein tyrosine kinases, such as those of transforming viruses, by interfering with or reversing cell transformation that is associated with the activity of a protein tyrosine kinase.

Antibody specific for a protein tyrosine phosphatase that localizes to focal adhesions

DNA encoding density enhanced protein tyrosine phosphatases

Novel protein tyrosine phosphatases in which the invariant aspartate residue is replaced with an alanine residue and which bind to a tyrosine phosphorylated substrate and are catalytically attenuated are described. Also described are methods of identifying tyrosine phosphorylated proteins which complex with the described protein tyrosine phosphatases.

Substrate trapping protein tyrosine phosphatases

DNA which encodes a protein homologous to the protein tyrosine phosphatases (PTPases) which catalyze the dephosphorylation of proteins in which tyrosyl residues have been phosphorylated through the action of a protein kinase. The protein, which appears as if it will localize to focal adhesions, is also the subject of the present invention. In particular, it relates to cDNA encoding a protein, referred to as PTPH1. Overexpression of PTPH1 may be a powerful approach to countering the effects of oncogenic protein tyrosine kinases, such as those of transforming viruses, and interfering with or reversing cell transformation. This would provide a means of preventing or reversing abnormally high levels of phosphotyrosine associated with any disease or condition, such as preventing or reversing malignancy associated with the activity of a protein tyrosine kinase. In the present method, DNA or RNA encoding PTPH1 or a functional equivalent of PTPH1 is administered to an individual in an appropriate gene transfer vehicle which can infect mammalian cells and, once inside the mammalian cells, express and make available PTPH1 or its functional equivalent in sufficient quantities to overcome or counteract the protein tyrosine kinase activity. As a result, phosphorylation of tyrosine residues at abnormal levels is prevented or reversed, resulting in turn in prevention or reversal of malignancy of cells.

Protein tyrosine phosphatase which localizes to focal adhesions

DNA which encodes a protein homologous to the protein tyrosine phosphatases (PTPases) which catalyze the dephosphorylation of proteins in which tyrosyl residues have been phosphorylated through the action of a protein kinase. The protein, which appears as if it will localize to focal adhesions, is also the subject of the present invention. In particular, it relates to cDNA encoding a protein, referred to as PTPH1.

Growing community of inventors

Huntington, NY, United States of America

Nicholas K Tonks