Skip to Main content Skip to Navigation
Journal articles

Tyrosine kinase syk non-enzymatic inhibitors and potential anti-allergic drug-like compounds discovered by virtual and in vitro screening.

Abstract : In the past decade, the spleen tyrosine kinase (Syk) has shown a high potential for the discovery of new treatments for inflammatory and autoimmune disorders. Pharmacological inhibitors of Syk catalytic site bearing therapeutic potential have been developed, with however limited specificity towards Syk. To address this topic, we opted for the design of drug-like compounds that could impede the interaction of Syk with its cellular partners while maintaining an active kinase protein. To achieve this challenging task, we used the powerful potential of intracellular antibodies for the modulation of cellular functions in vivo, combined to structure-based in silico screening. In our previous studies, we reported the anti-allergic properties of the intracellular antibody G4G11. With the aim of finding functional mimics of G4G11, we developed an Antibody Displacement Assay and we isolated the drug-like compound C-13, with promising in vivo anti-allergic activity. The likely binding cavity of this compound is located at the close vicinity of G4G11 epitope, far away from the catalytic site of Syk. Here we report the virtual screen of a collection of 500,000 molecules against this new cavity, which led to the isolation of 1000 compounds subsequently evaluated for their in vitro inhibitory effects using the Antibody Displacement Assay. Eighty five compounds were selected and evaluated for their ability to inhibit the liberation of allergic mediators from mast cells. Among them, 10 compounds inhibited degranulation with IC(50) values ≤10 µM. The most bioactive compounds combine biological activity, significant inhibition of antibody binding and strong affinity for Syk. Moreover, these molecules show a good potential for oral bioavailability and are not kinase catalytic site inhibitors. These bioactive compounds could be used as starting points for the development of new classes of non-enzymatic inhibitors of Syk and for drug discovery endeavour in the field of inflammation related disorders.
Document type :
Journal articles
Complete list of metadatas

Cited literature [18 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-00610280
Contributor : Yves Le Ster <>
Submitted on : Thursday, July 21, 2011 - 2:46:09 PM
Last modification on : Friday, March 27, 2020 - 3:22:22 AM
Long-term archiving on: : Friday, November 4, 2011 - 3:07:44 PM

File

Plos_ONE_in_press.pdf
Files produced by the author(s)

Identifiers

Citation

Bruno Villoutreix, Guillaume Laconde, David Lagorce, Pierre Martineau, Maria Miteva, et al.. Tyrosine kinase syk non-enzymatic inhibitors and potential anti-allergic drug-like compounds discovered by virtual and in vitro screening.. PLoS ONE, Public Library of Science, 2011, 6 (6), pp.e21117. ⟨10.1371/journal.pone.0021117⟩. ⟨inserm-00610280⟩

Share

Metrics

Record views

526

Files downloads

891