The epidermal growth factor receptor (EGFR) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The EGFR family of receptor tyrosine kinases (RTK) comprises four distinct receptors: the EGFR (also known as ErbB-1/HER1), ErbB-2 (neu, HER2), ErbB-3 (HER3) and ErbB-4 (HER4). Besides, the ErbB family of RTKs couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. In many cancer types, mutations affecting EGFR expression or activity could result in cancer. Non-small cell lung cancer (NSCLC) is the most frequent cause of death among patients with malignant lung tumors. The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) used worldwide to treat advanced NSCLC with sensitizing EGFR mutations.

Almonertinib (also known as HS-10296) is an orally active, irreversible, and third-generation EGFR tyrosine kinase inhibitor.

Almonertinib is a pyrimidine-based compound that binds covalently and irreversibly to cysteine-797 at the adenosine triphosphate-binding site of the EGFR tyrosine kinase domain. In addition, Almonertinib is highly selective for EGFR-sensitizing and T790M resistance mutations. Specifically, Almonertinib shows great inhibitory activity against T790M, T790M/L858R and T790M/Del19 (IC50 values of 0.37 nM, 0.29 nM and 0.21 nM, respectively), and is less effective against wild type (IC50 of 3.39 nM).  Furthermore, Almonertinib (20 mg/kg; orally; once daily; for 14 days) inhibits the growth of transplanted National Cancer Institute-H1975 tumor cells (L858R and T790M mutation positive) in mice, and the tumor growth inhibition rate is 194.4%. Moreover, Almonertinib has no additional toxicities occur in rats and dogs. Importantly, Almonertinib has the potential for the research of the non-small cell lung cancer (NSCLC).

In summary, Almonertinib is an orally active, and third-generation EGFR inhibitor that targets both EGFR-sensitizing and T790M resistance mutations.

References:

[1] James Chih-Hsin Yang, et al. J Thorac Oncol. 2020 Dec;15(12):1907-1918.