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NVP-BHG712: Effects of regioisomers on the affinity and selectivity towards the EPHrin family.

08:00 EDT 21st June 2018 | BioPortfolio

Summary of "NVP-BHG712: Effects of regioisomers on the affinity and selectivity towards the EPHrin family."

EPH receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates the 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 the Novartis inhibitor 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 methylation on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Further, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity.

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Name: ChemMedChem
ISSN: 1860-7187
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Medical and Biotech [MESH] Definitions

A transmembrane domain containing ephrin that binds with high affinity to EPHB1 RECEPTOR; EPHB3 RECEPTOR; and EPHB4 RECEPTOR. Expression of ephrin-B2 occurs in a variety of adult tissues. During embryogenesis, high levels of ephrin-B2 is seen in the PROSENCEPHALON; RHOMBENCEPHALON; developing SOMITES; LIMB BUD; and bronchial arches.

An ephrin that was originally identified as the product of an early response gene induced by TUMOR NECROSIS FACTORS. It is linked to the CELL MEMBRANE via a GLYCOINOSITOL PHOSPHOLIPID MEMBRANE ANCHOR and binds EPHA2 RECEPTOR with high affinity. During embryogenesis high levels of ephrin-A1 are expressed in LUNG; KIDNEY; SALIVARY GLANDS; and INTESTINE.

A GLYCOINOSITOL PHOSPHOLIPID MEMBRANE ANCHOR-containing ephrin with a high affinity for the EPHA3 RECEPTOR. Early in embryogenesis it is expressed at high levels in the MESENCEPHALON; SOMITES; branchial arches, and LIMB BUDS.

A transmembrane domain containing ephrin. Although originally found to be specific for the EPHB3 RECEPTOR it has since been shown to bind a variety of EPH FAMILY RECEPTORS. During embryogenesis ephrin-B3 is expressed at high levels in the ventral neural tube. In adult tissues, it is found primarily in the BRAIN and HEART.

A GLYCOINOSITOL PHOSPHOLIPID MEMBRANE ANCHOR containing ephrin with a high affinity for the EPHA3 RECEPTOR; EPHA5 RECEPTOR; EPHA6 RECEPTOR; EPHA7 RECEPTOR; and EPHA8 RECEPTOR. It is found primarily in NERVE TISSUE.

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