Capillary electrophoresis and microscale thermophoresis in fragment-based drug discovery : development of screening bioassays towards FXIIa

Tackling thrombotic disorders without affecting the hemostatic capacity remains a challenge in medicine. One of the strategies in the search for safer antithrombotic therapies is to target coagulation factor XIIa (FXIIa).[1] This strategy have two substantial advantages : 1. No bleeding risk 2. Additional anti-inflammatory effects After limited results with the traditional medicinal chemistry approach (inhibitors in the μM range) [2], we decided to apply fragment-based drug discovery approach (FBDD). In its first step, FBDD strongly depends on the ability to detect and gauge weak affinity binders. In the scope of validating the fragment hits, the most robust strategy is to apply orthogonal techniques. In this work, we investigate the suitability of microscale thermophoresis and capillary electrophoresis for the discovery of new fragments that bind FXIIa. [1] a) J.I.Weitz, Thromb Res, 141 Suppl 2 (2016) S40-45; b) J.C. Fredenburgh, P.L. Gross, J.I. Weitz, Blood, 129 (2017) 147-154; c) A.T. Long, E. Kenne, R. Jung, T.A. Fuchs, T. Renne, J Thromb Haemost, 14 (2016) 427-437. [2] a) S. Robert, C. Bertolla, B. Masereel, J.M. Dogné, L. Pochet, Journal of Medicinal Chemistry, 51 (2008) 3077-3080; b) C. Bouckaert, S. Serra, G. Rondelet, E. Dolušić, J. Wouters, J.M. Dogné, R. Frédérick, L. Pochet, Eur J of Med Chem, 110 (2016) 181-194Development of new compounds targeting coagulation factor XIIa using innovative microfluidic assays in the context of fragment-based drug discover