Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is a type III receptor tyrosine kinase (RTK) in the PDGFR family. VEGF preferably binds this receptor and triggers important signaling pathway implicated in the process of vasculogenesis and angiogenesis. VEGFR2 is a clinically validated target to treat Renal Cell Carcinoma (RCC). In addition to efficacy seen in RCC, VEGF signaling inhibition has been associated to side effects, in particular hypertension, consistently observed for Tyrosine Kinase Inhibitors (TKI) and the monoclonal antibody bevacozumab. Both efficacy and safety profiles of approved VEGFR TKI depend on their selectivity profile, which has been clinically confirmed in a published comparative study. Recently the crystal structures of sunitinib and sorafenib, two clinically relevant TKIs, bound to the kinase domain of VEGFR2 have been solved together with the enzyme JM domain, highlighting the critical role played by this domain to form the inactivated state of VEGFR2 kinase which binds these ligands. The construct utilized to generate these VEGFR2 crystal structures was also used to determine the potencies, time dependencies and selectivity of a wide panel of TKI, including sunitinib and sorafenib. Besides, kinetic parameters (koff) were detected for both these inhibitors and the new construct. While sunitinib is a prototypical type IV inhibitor, showing short dissociative half-life from VEGFR2, sorafenib is an exemplar of type II inhibitor, characterized by long dissociative half-life from VEGFR2 receptor. The objectives of this study consisted in elucidating the unbinding pathway of the prototypical VEGFR2 inhibitors sunitinib and sorafenib from VEGFR2 with the use of steered-molecular dynamics (SMD) and in identifying a qualitative relationship between the calculated unbinding energies (DeltaGoff) and their experimental rate of dissociation (koff) from VEGFR2. Furthermore, atomistic details of the unbinding pathways have been collected and analyzed in detail.

Modelling studies of VEGFR2 and its inhibitors

248th National Meeting (2014)

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