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Theoretical background: The human epidermal growth factor (EGF) receptor HER4 / ErbB4 is part of the ErbB family of receptor tyrosine kinases. HER4 / ErbB4 is ativated by both, heregulins and some of the EGF ligands, providing a variability in receptor activation by a diversity of monomers and heterodimers. Upon dimerization the receptor kinase undergoes autophosphorylation at tyrosine residues within the intracellular domain, acting as binding sites for proteins e.g. Shc, Grb2, Src, PI3K, SHP1 and SHP2. ErbB4 signaling is accompanied by cleavage and release of the ErbB4 soluble intracellular domain (4ICD) which upon translocation into the nucleus can associate with transcriptional regulators (YAP, STAT5). The expression of ErbB4 is generally low in most breast cancer cell lines and the kinase may function as a tumor suppressor.


ErbB4 and inhibitors: Several small molecule ErbB inhibitors based on a quinazoline structure and monoclonal antibodies have been developed. Whereas drugs such as Erlotinib and Gefitinib bind to the ATP binding site of ErbB receptors adopting an active structure, the compound Lapatinib preferentially binds to the inactive kinase conformation (ErbB4: Erlotinib: IC50 = 230 nM, Lapatinib: IC50 = 54 nM [1]). Furthermore, Dasatinib, initially designed as Src kinase inhibitor has a high affinity for ErbB4 (IC50 = 55 nM). SKLB1206, a novel reversible EGFR inhibitor, has potent activity against EGFR with gefitinib-sensitive and -resistant (T790M) mutations and also for ErbB2, ErbB4 and VEGFR2 [2].

Figure: Real-time kinetic analysis of kinase inhibitor Dasatinib binding to ERbB4 using surface plasmon resonance.


[1] Davis MI et al. (2011) Nat Biotechnol.29(11):1046-51.

[2] Pan Y et al. (2012) Mol Cancer Ther. 11(4):952-62.


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