NVP‐BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family |
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| Authors: | Alix Tröster Dr Stephanie Heinzlmeir Benedict‐Tilman Berger Dr Santosh L Gande Dr Krishna Saxena Dr Sridhar Sreeramulu Verena Linhard Dr Amir H Nasiri Dr Michael Bolte Dr Susanne Müller Prof?Dr Bernhard Kuster Dr Guillaume Médard Dr Denis Kudlinzki Prof?Dr Harald Schwalbe |
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| Affiliation: | 1. Center for Biomolecular Magnetic Resonance (BMRZ), Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany;2. Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany;3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany;4. Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany;5. Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Frankfurt am Main, Germany;6. Institute for Inorganic Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany |
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| Abstract: | Erythropoietin‐producing hepatocellular (EPH) receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion, and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of NVP‐BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application. They only differ by the localization of a single methyl group on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Furthermore, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity. |
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| Keywords: | EPH receptors medicinal chemistry NMR spectroscopy structural biology X-ray crystallography |
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