Asthmakine– Small molecule IL-4/IL-13 protein-protein interaction inhibitors for asthma – Asthmakine

IL-4 and IL-13 play key roles in the pathogenesis of asthma and are appealing therapeutic targets for the treatment of asthma. These cytokines interact with a common partner, IL-4Ra, within two types of activated trimers and can thus be modulated simultaneously. Dupilumab, a human monoclonal antibody targeting IL-4Ra, was recently approved and marketed for the treatment of asthma.
However, a small molecule acting as an inhibitor of the IL-4/IL-13 protein-protein interactions will be a complementary asset in the asthma therapeutic arsenal. It could be used with the same therapeutic benefits than dupilumab (for patients that remain uncontrolled with available first-line asthma therapies) but with, notably, a better control of side-effects, an easier administration using the oral route and a smaller burden for healthcare systems. This small molecule could also provide a therapeutic alternative
Currently, there is no small-molecule IL-4/IL-13 protein-protein interactions inhibitor on the market nor in clinical development and the first small-molecule IL-4/IL-13 protein-protein interactions inhibitor was described in the scientific literature in 2020.
The objective of this project is the discovery of a small-molecule IL-4/IL-13 protein-protein interactions inhibitor, characterized by a preclinical ADMET profile and a therapeutic proof of concept in animal models representative of asthma pathology.
The Asthmakine project is based on a preliminary study carried out by one project partner in which a potential binding site at the interface between IL-4 and the other two proteins forming the activated trimer was identified. This binding site is characterized by a relevant druggability score and is conserved within the structure of the IL-13 activated trimer. A docking study targeting this binding site was conducted using a database of nearly 10000 approved drugs and proprietary compounds synthesized in the GBCM laboratory. Three GBCM proprietary compounds were ranked among the best docked molecules and the inhibition of the binding induced by these 3 compounds on IL-4 and IL-13 was evaluated using in vitro assays. This hierarchical in silico / in vitro screening led to the identification of one proprietary small-molecule IL-4/IL-13 protein-protein interactions inhibitor. This compound will be our hit molecule for further optimization in the Asthmakine project.
The first step of the Asthmakine project will consist in rational design, synthesis and in vitro evaluation of binding inhibition on IL-4 and IL-13 of 70 new molecules. The aim of this step is to optimize the hit molecule by improving simultaneously its activity and its physicochemical profile. In a second step, 5 optimized hit compounds will be selected and their in vitro ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity) profile will be determined. Using these results, in the third step of the Asthmakine project, 2 lead compounds will be evaluated in validated in vivo humanized mice asthma models (hIL-4/hIL-4Ra/hIL13) according to their hIL-4 and hIL-13 binding potency. The major asthma hallmarks, namely airway inflammation, mucus, Th2 cytokine and IgE production will be assessed in order to select a therapeutic small-molecule IL-4/IL-13 protein-protein interactions inhibitor that can be further developed in a regulatory preclinical program.
This project involves 3 partners that will respectively manage (1) medicinal chemistry and molecular modeling, (2) biochemical assays and (3) in vivo assays experiments to deliver a robust preclinical proof of concept.