2. Academic Validation
  3. NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family

NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family

  • ChemMedChem. 2018 Aug 20;13(16):1629-1633. doi: 10.1002/cmdc.201800398.
Alix Tröster 1,  Stephanie Heinzlmeir 2 3,  Benedict-Tilman Berger 4 5,  Santosh L Gande 1 3,  Krishna Saxena 1,  Sridhar Sreeramulu 1,  Verena Linhard 1,  Amir H Nasiri 1,  Michael Bolte 6,  Susanne Müller 4,  Bernhard Kuster 2 3,  Guillaume Médard 2,  Denis Kudlinzki 1 3,  Harald Schwalbe 1 3
Affiliations

Affiliations

  • 1 Center for Biomolecular Magnetic Resonance (BMRZ), Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe University, Max-von-Laue-Straße 7, 60438, Frankfurt am Main, Germany.
  • 2 Chair of Proteomics and Bioanalytics, Technical University of Munich, Emil-Erlenmeyer-Forum 5, 85354, Freising, Germany.
  • 3 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, 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, Max-von-Laue-Straße 9, 60438, Frankfurt am Main, Germany.
  • 6 Institute for Inorganic Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.
PMID: 29928781 DOI: 10.1002/cmdc.201800398
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.

Keywords

EPH receptors; NMR spectroscopy; X-ray crystallography; medicinal chemistry; structural biology.

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