A REVIEW ON: THE DESIGN AND DEVELOPMENT OF EGFR TYROSINE KINASE INHIBITORS IN CANCER THERAPY

Cancer chemotherapy has entered a new era of molecularly targeted therapeutics, in which structure based approaches are employed to create small molecule. This design has been successfully applied for the making of drugs for epidermal growth factor receptor tyrosine kinase (EGFR-TK). The rationale to inhibit the EGFR-TK family as an approach to cancer therapy has continued to grow stronger over the last 20 years. Recently significant progresses have been made in the area of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Overexpression of EGFR has been shown to promote cell proliferation and growth, metastasis, angiogenesis, inhibition of apoptosis and resistance to standard cytotoxic therapies. The EGFR gene family is of eminent importance as prognostic marker in cancer patients. Four members have been identified in humans erbB1-erbB4 (HER1-HER4), of which HER1 (EGFR, erbB1) and HER2 (erbB2, C-neu) are best characterized. EGFR overexpression is seen in breast cancer, ovarian cancer, lung cancer and prostate cancer. Currently the most useful inhibitors of the EGFR family are derived from three chemical series which include 4-anilino-quinazolines, 4-[ar(alk)yl amino]pyridopyrimidines and 4-phenyl amino pyrrolo-pyrimidines. EGFR tyrosine kinase inhibitors in development include anti EGFR monoclonal antibodies such as cetuximab (Erbitux) and small molecule inhibitors such as gefitinib (Iressa) and erlotinib(Tarceva). Many more EGFR-TKIs are still under evaluation in clinical trials for the treatment of cancer. This review discusses the current status of EGFR-TKIs and their design, development in cancer therapy.

KEY WORDS : EGFR, cancer, tyrosine kinase, monoclonal antibodies, small molecule inhibitors