Development of inhibitors for pathological angiogenesis targeting the VEGF pathways

The formation of new blood vessels by pathological angiogenesis is an important process for the progression of various human diseases, such as cancers and retinopathy. Vascular endothelial growth factor (VEGF) is a key molecule for the formation of new blood vessels. Indeed, these diseases already benefit form anti-VEGF angiogenesis inhibitors, but novel and better inhibitors are necessary. Therefore, understanding the molecular mechanisms of blood vessel formation is an important step towards the development of new therapies for the various diseases that have angiogenesis as a common element for the onset and progression of the disease. In particular, the role of the different VEGF family members and their interaction with their three tyrosine kinase receptors.

We have recently identified peptides targeting various angiogenic receptors (VEGFR1, VEGFR2 and VEGFR3) and identified small molecules targeting the VEGF pathway. Here, we will perform a drug fragment screening using nuclear magnetic resonance (NMR) on VEGFR1, a less studied VEGF-receptor, to search for small molecules with anti-angiogenesis potential. We will conduct the fragment screening on the ligand binding Ig domain of VEGFR1 (VEGFR1-D2). A DSI-poised Library containing 768 small molecule fragments will be screened using NMR. Changes in T2 relaxation, 1D proton and solvent-exposed ligand protons (Water Logsy) of each individual fragment will be analyzed in the presence and absence of VEGFR1-D2 (10 µM).

We aim to identify small molecule binders of VEGFR1 to explore the chemical and target space of this angiogenesis related receptor. The study of such interactions became fundamental to better understand the role of this receptor in pathological angiogenesis, and may also lead to the development of new drugs and the improvement of the current angiogenesis therapies.