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  • In particular EphB has been


    In particular, EphB4 has p0035 been one of the most studied receptor of the Eph family: inhibition of EphB4 expression using interfering-RNA or antisense oligonucleotides inhibited proliferation, survival and invasion of PC3 prostate cancer p0035 in vitro and in vivo. Inhibition of EphB4 signalling using soluble extracellular-domains of EphB4 have also been shown to inhibit tumour growth in xenograft studies. Transgenic studies have shown that EphB4 and its associated ligand ephrin B2 cause embryonic lethality associated with vascular modelling defects. Finally, interference with endothelial EphB4 signalling altered tumour blood vessel morphology in tumour models. These observations suggest that EphB4 in particular may play a critical role in tumour angiogenesis and tumour growth. However, the functional significance of EphB4 is far from being fully understood: for instance, tumour-suppressor as well as tumour-promoting activities have been proposed for EphB4 in breast cancer. In addition, by contrast with most receptor tyrosine kinases, signalling can originate from the ephrin ligands as well as from the Eph receptors; bi-directional signalling has emerged as an important mechanism by which Eph receptors and ephrin ligands control the output signal in processes of cell–cell communication. The relative contribution of these ‘forward’ and ‘reverse’ signals in tumour vascularisation and tumour growth has not been fully clarified., In our search for EphB4 kinase inhibitors as potential oncology drugs, we had recently identified 4-(benzodioxolyl)amino pyrimidines such as compounds and as potent EphB4 kinase inhibitors (). Previous reports have linked the benzodioxole scaffold with mechanism based P450 inhibition, which might lead to drug–drug interactions or toxicological events. This potential risk was confirmed by the following evidence: and showed some CYP inhibition (resp. IC 2.6 and 0.9μM against 3A4, fluorometric assay) with evidence of time dependant inhibition. X-ray crystal structure of bound to the EphB4 kinase domain has established that the benzodioxole group is buried in the selectivity pocket, the hydrophobic region beyond the Thr693 gatekeeper residue. As a consequence, variation of this group may highly impact EphB4 potency and selectivity versus other kinases.
    Main Text To ensure high-fidelity, short-range communication between adjacent cells, ligand molecules are expressed on the surface of one cell, and the receptor is expressed on the surface of the proximal target cell. Because juxtacrine signaling requires the formation of a ligand-receptor complex precisely where two cells form an intimate physical touch, signal transmission is heavily influenced by physical processes that transcend conventional one-ligand one-receptor binding. For example, higher-order molecular processes such as oligomerization (1, 2), spatial organization/confinement (3), and mechanotransduction (4) figure into juxtacrine signaling. A prominent family of receptors that signal through a juxtacrine mechanism are the erythropoietin-producing human hepatocellular (Eph) receptors and their membrane-bound ligands, the ephrins. Eph receptors represent the largest family of receptor tyrosine kinases (RTKs) and play an integral role in neuronal development and patterning. As is the case for the vast majority of juxtacrine-signaling receptors, the Eph RTKs are particularly sensitive to oligomerization state (5), spatial localization (6), and confinement as well as mechanical interactions (3, 7, 8). The EphB4 member of the Eph family, along with its membrane-associated ligand, ephrin-B2, regulates neural stem cell proliferation and survival (9). As neural-stem-cell-mediated adult neurogenesis plays important roles in learning and memory (10), elucidating the molecular pathways that drive neural stem cell self-renewal may lead to new therapeutic strategies to treat neurological disease. This underscores the importance of studying the regulation of EphB4 signaling in neural stem cells.