Structure-based drug repositioning reveals ibrutinib as VEGFR2 inhibitor

Adasme, M. F.; Parisi, D.; Van Belle, K.; Salentin, S.; Haupt, V. J.; Jennings, G. S.; Heinrich, J.-C.; Herman, J.; Sprangers, B.; Louat, T.; Moreau, Y.; Schroeder, M.

doi:10.1101/678896

bioRxiv · 10.1101/678896

Structure-based drug repositioning reveals ibrutinib as VEGFR2 inhibitor

Adasme, M. F.·Parisi, D.·Van Belle, K.·Salentin, S.·Haupt, V. J.·Jennings, G. S.·Heinrich, J.-C.·Herman, J.·Sprangers, B.·Louat, T.·Moreau, Y.·Schroeder, M.

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Abstract

Many drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Brutons tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinibs anti VEGFR2 action through a specific pattern of interactions shared between BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen.

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Adasme, M. F., Parisi, D., Van Belle, K., Salentin, S., Haupt, V. J., Jennings, G. S., Heinrich, J.-C., Herman, J., Sprangers, B., Louat, T., Moreau, Y., Schroeder, M.. 2019-06-21. Structure-based drug repositioning reveals ibrutinib as VEGFR2 inhibitor. https://doi.org/10.1101/678896

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