Development of new compounds targeting coagulation factor XIIa using innovative microfluidic assays in the context of fragment-based drug discovery

Recently, the contact phase of blood coagulation was highlighted as an
attractive target for the development of new antithrombotic drugs with low
rates of therapy-related hemorrhages. In this project, we aim to develop
selective inhibitors of FXIIa, a serine protease implicated in this pathway. A
fragment-based drug discovery (FBDD) approach will be followed and the
research program can be divided in three major steps. The objective of the
first step is to select the best fragments that can be used for the evolution
process. For this purpose, we will set up microfluidic bioassays based on
capillary electrophoresis and microscale thermophoresis. These tests will be
built to identify and rank weak affinity binder from a fragment library. This
library will be composed of up to 2000 fragments with criteria to ensure
chemical diversity and good physicochemical properties. In the second step,
we will optimize the identified fragments to obtain lead compounds. This
process will be guided by computer-aided drug design and structure activity
and selectivity relationship. The evaluation of the anticoagulant properties
(step 3) of our compounds will be done by (1) in vitro enzymatic assays on
isolated coagulation factors (i.e. thrombin, factor Xa, tissue factor/factor VIIa
complex, FXIa, plasma kallikrein and factor XIIa); (2) by functional ex vivo
coagulation assays (thrombin generation and clotting time assays in
plasma, microfluidics model on whole blood) and (3) by in vivo venous and
arterial thrombosis models. In conclusion, this project will provide new
potent and selective FXIIa inhibitors that can be used as pharmacological
tools for further studying FXIIa. During this research we will also set up and
validate innovative fragment screening assays.