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Novel non enzymatic inhibitors of syk tyrosine kinase

Reference

86236-02

Patents status

French patent application FR0801959 filed on April 9, 2008 and entitled “Molécules inhibant une voie métabolique impliquant la protéine tyrosine kinase Syk et procédé d’identification de ces molécules”
FR2929851

Inventors

Piona DARIAVACH
Bruno VILLOUTREIX
Pierre MARTINEAU

commercial status

Research agreement, exclusive or non exclusive licenses

Laboratory

Institut de recherche en cancérologie de Montpellier (IRCM, INSERM U896), Montpellier, France and Molécules thérapeutiques in silico (MTi, INSERM U973), Paris, France.

Description

CONTEXT

The critical position of Spleen Tyrosine Kinase (Syk) upstream to immunoreceptor signaling complexes that regulate inflammatory responses in leukocytes suggests that it could be an excellent target for treating allergic disorders. Pharmacological inhibitors of Syk kinase activity bearing therapeutic potential have been developed. However, inhibiting the catalytic activity of this kinase leads to unwanted consequences of on various physiological functions such as cell differentiation, adhesion and proliferation. Thus there is still a need in developing new approaches for the discovery of a novel class of safer and yet effective Syk inhibitors.

TECHNICAL DESCRIPTION

This invention describes new organic molecules which bind to a newly defined pocket of Syk, and at the vicinity of the epitope of anti-Syk scFv antibody G4G11. We have previously studied the inhibitory effects of the anti-Syk intracellular antibody G4G11 on FcepsilonRI-induced release of allergic mediators. Small molecules were selected from a compound collection on the basis of their ability to displace the binding of scFv G4G11 to Syk. These drug-like compounds do not inhibit the catalytic activity of Syk.

DEVELOPMENT STAGE

Design and selection of in vivo protein-protein inhibitors is a new and very active trend in pharmacology. To address this topic, our team has been investigating the use of Intracellular Antibodies. We have developed the use of intrabodies for high-throughput screening of new classes of specific drugs (US patent WO2005106481). The approach based on an Antibody Displacement Assay was used to identify from a compound collection, functional mimics of anti-Syk scFv G4G11 that act as potential inhibitors of the allergic response. We discovered C-13, a small molecule that inhibits FcepsilonRI-induced mast cell degranulation in vitro and anaphylactic shock in vivo. Structural analysis, docking and site directed mutagenesis allowed us to identify the binding cavity of C-13, located at the interface between the two SH2 domains and the interdomain A of Syk. We have performed an in silico docking of a compound collection of 350.000 molecules into this newly described pocket. Based on their in vitro inhibitory effects evaluated using the Antibody Displacement Assay, 87 compounds were selected and they were further characterized in vivo in a degranulation assay in mast cells. The binding of the compounds to Syk was measured using fluorescence spectroscopy. This has led to the isolation of several new classes of non-enzymatic inhibitors of Syk that may have interesting applications in the field of allergy and inflammation.

BENEFITS

This invention is dedicated to improve the selectivity of anti-Syk therapies by impeding the interaction of Syk with its cellular partners, instead of targeting its catalytic site.

INDUSTRIAL APPLICATIONS

The molecules described in this invention can be used to the prevention and the treatment of pathologies involving the tyrosine kinase Syk, mainly autoimmune and inflammatory diseases, allergies and cancer.

 


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