Journal
CHEMMEDCHEM
Volume 13, Issue 16, Pages 1629-1633Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800398
Keywords
EPH receptors; medicinal chemistry; NMR spectroscopy; structural biology; X-ray crystallography
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Funding
- German Consortium for Translational Cancer Research (DKTK)
- DFG [SFB807]
- EU
- state of Hesse
- Structural Genomics Consortium (SGC) [1097737]
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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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