Development of novel 4"-alkyl EGCG derivatives as a third generation EGFR tyrosine kinase inhibitor to overcome from drug resistance for the cancer treatment

Abstract

The epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase family and hold a significant role in normal cell proliferation, division, and migration [1]. Aberrant activation of EGFR leads to the progression of various types of cancer including non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, pancreatic cancer etc [1]. Therefore, EGFR have been known as a key druggable target for the cancer therapy. Remarkable progresses have been made in the EGFR drug discovery in the last two decades. Currently, there are two approved categories of EGFR targeted therapy, small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) [2]. EGFR-TKIs are the ATP binding site inhibitors which ultimately leads to the blockade of phosphorylation of EGFR and its associated downstream signaling pathways including PI3K/AKT, RAS/RAF/MEK/ERK and STATs. On the other hand, mAbs binds to the ligand binding site and prevents the homodimerization or heterodimerization [2]. The first EGFR-TKI, gefitinib, received the food and drug administration (FDA) approval in the year 2003, was the breakthrough in the era of cancer drug discovery [1]. Unfortunately, after 10-15 months of progression free survival patients started to develop drug resistance. Major reason behind the drug resistance was the emergence of gatekeeper mutation (T790M) and the reversible nature of gefitinib was found [1]. Subsequently, afatinib and dacomitinib an irreversible second-generation EGFR-TKI have been introduced to address the resistant nature of EGFR against first-generation TKIs.