The epidermal growth factor receptor (EGFR) belongs to the ErbB family (also known as the EGFR family) of receptor tyrosine kinases (RTK). EGFR family comprises four distinct receptors: the EGFR (ErbB1, HER1), ErbB-2 (HER2, neu in rodents), ErbB-3 (HER3) and ErbB-4 (HER4). It is worth mentioning that EGFR family members distinguish themselves from other RTKs in having an intracellular juxtamembrane domain that activates the receptor and a very large carboxy-terminal tail that contains autophosphorylation sites and serves an autoregulatory function. EGFR family couples binding of extracellular growth factor ligands to intracellular signaling pathways. And they can regulate diverse biologic responses, including proliferation, differentiation, cell motility, and survival.
EGFR and its relatives are known oncogenic drivers in cancers such as lung cancer, breast cancer, and glioblastoma. Inhibitors of these receptors have been among the most successful examples of targeted cancer therapies to date, including antibody therapeutics and small-molecule tyrosine kinase inhibitors. Meanwhile, the effect of knocking out the EGFR gene in mice ranges from embryonic lethality in one genetic background to death at birth in another, to postnatal death in yet another. What’s more, ErbB 2/3/4 signaling has a key role in both cardiac development and maintenance of cardiac function.
Avitinib is a potent and irreversibl inhibitor of EGFR.
Avitinib is a potent, irreversible and orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Importantly, it is selective for EGFR-active and T790M mutations, exhibiting a 298-fold increase in potency compared with wild-type EGFR. Meanwhile, Avitinib is well tolerated and efficacious in vivo. In a xenograft model, oral administration of 500 mg/kg avitinib can result in complete remission of tumors with EGFR-active and T790M mutations. However, its concentration in CSF is low, and the penetrability of BBB is weak.
All in all, Avitinib is a potent, selective, irreversible and orally active inhibitor of EGFR. Avitinib has comparable anti-tumor activity and tolerated toxicity.
Reference:
[1]. Lemmon MA, et, al. Cold Spring Harb Perspect Biol. 2014 Apr 1;6(4):a020768.