Epidermal growth factor receptor (EGFR), Human epidermal growth factor receptor 2 (HER2), and Human epidermal growth factor receptor 4 (HER4) kinase domains (EGFR/HER2/HER4 kinase domains)

The EGFR, HER2, and HER4 kinase domains are the intracellular catalytic components of the ErbB family of receptor tyrosine kinases, which are critical regulators of cell growth, survival, and differentiation [1, 10, 12]. These domains exhibit intrinsic tyrosine kinase activity that is activated upon ligand-induced or mutation-driven receptor dimerization, leading to the phosphorylation of downstream signaling cascades such as the PI3K/Akt and MAPK/ERK pathways [7, 12, 17]. Overexpression or activating mutations in these kinase domains are frequently observed in various cancers, including non-small cell lung cancer and HER2-positive breast cancer, driving aggressive tumor progression [4, 9, 15]. Therapeutic strategies often employ pan-HER inhibitors, such as afatinib and neratinib, which are small molecules designed to bind to the ATP-binding pockets of these domains, thereby blocking their catalytic activity and suppressing oncogenic signaling [1, 3, 14]. While effective, the simultaneous inhibition of multiple ErbB family members can lead to significant side effects, most notably gastrointestinal and dermatological toxicities, due to the inhibition of wild-type receptors in normal tissues [16, 21, 22].

Other names

ErbB1/ErbB2/ErbB4 kinase domainsPan-HER kinase domainsPan-ErbB kinase domainsHER1/HER2/HER4 kinase domains

Irreversible or reversible inhibition of tyrosine kinase activity by binding to the ATP-binding pocket of the intracellular kinase domains, preventing autophosphorylation and downstream signaling [1, 2, 14].