Icotinib Hydrochloride is a potent and highly selective inhibitor of epidermal growth factor receptor tyrosine kinases (EGFR-TKI) with IC50 value of 5 nM.
EGFR is an oncogenic driver which is expressed on the cell surface of normal cells and cancer cells [1], and patients with somatic mutations, particularly an exon 19 deletion or exon 21 L858R mutation, within the tyrosine kinase domain have activating mutations that lead to unchecked cell proliferation.[2] Overexpression of EGFR caused inappropriate activation of the anti-apoptotic Ras signaling pathway, found in many different types of cancer.[3]
Icotinib is a quinazoline derivative that binds reversibly to the ATP binding site of the EGFR protein, preventing completion of the signal transduction cascade.[4] Icotinib inhibited the intracellular phosphorylation of tyrosine kinase(TK) associated with the epidermal growth factor receptor (EGFR).[5]
Icotinib is indicated for the treatment for EGFR mutation-positive, advanced or metastatic non-small cell lung cancer (NSCLC) as a second-line or third-line treatment, for patients who have failed at least one prior treatment with platinum-based chemotherapy.[6]
References:
1.A Douglas Laird,and Julie M Cherrington. Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. 2003, 12(1): 51-64.
2.Raymond E, Faivre S, Armand JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 2000;60 Suppl 1:15-23.
3.Sordella,R. "Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways". Science ,2004, 305 (5687): 1163-1167.
4.Bulgaru AM. et al. Erlotinib (Tarceva): a promising drug targeting epidermal growth factor receptor tyrosine kinase. Expert Rev Anticancer Ther. 2003 Jun;3(3):269-79.
5.Dudek AZ.et al. Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer. Lung Cancer. 2006, 51(1):89-96.
6.C Delbaldo, S Faivre, E Raymond. Les inhibiteurs des récepteurs de l’Epidermal Growth Factor (EGF) Epidermal growth factor inhibitors. La Revue de Médecine Interne. 2003,24(6): 372–383.