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NVP‐BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family
Author(s) -
Tröster Alix,
Heinzlmeir Stephanie,
Berger BenedictTilman,
Gande Santosh L.,
Saxena Krishna,
Sreeramulu Sridhar,
Linhard Verena,
Nasiri Amir H.,
Bolte Michael,
Müller Susanne,
Kuster Bernhard,
Médard Guillaume,
Kudlinzki Denis,
Schwalbe Harald
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800398
Subject(s) - erythropoietin producing hepatocellular (eph) receptor , ephrin , extracellular , intracellular , eph receptor a2 , kinase , tyrosine kinase , receptor , biochemistry , receptor tyrosine kinase , biology , selectivity , chemistry , transmembrane protein , structural isomer , stereochemistry , microbiology and biotechnology , catalysis
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.