Pyrimidine-based EGFR TK inhibitors in targeted cancer therapy.

Abstract Despite significant improvements of new treatment options, cancer continues to represent as one of the most common and fatal disease. The EGFR signaling pathway is considered as a significant approach in targeted therapy of cancers. Blocking the EGFR-driven pathway by inhibition the intracellular tyrosine kinase domain of EGFR showed considerable improvement in cancer therapy. In an effort to identify EGFR tyrosine kinase inhibitors (TKI), several small molecules especially pyrimidine containing derivatives have been designed by applying molecular simulation and evaluated which mostly showed promising inhibitory activity and selectivity. However, the emergence of epigenetic mutation and resistance problems restricted the long-term effectiveness of such medication and explained the need for further investigations in this field. In recent years, the studies have been focused on genetic alterations on EGFR tyrosine kinase domain, which led to the design and synthesis of more selective and effective inhibitors. Herein, we give an overview of the importance and status of EGFR inhibitors in cancer therapy. In addition, we provide an update of the recent advances in design, discovery and development of novel pyrimidine containing compounds as promising selective EGFR TK inhibitors.