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The development and clinical application of TK domain inhibitors (TKIs)provide important insights into the broader field of cancer-targeted therapies.To discuss the recent advances in the atomic level understanding of EGFR TK domainmutations, we aim at highlighting the current and future importance of these studieson malignancies where the TK domain is improperly activated. The analysis is conductedon published TK domain crystal structures deposited in the Protein Data Bank,or homology structures generated by homology modeling and AutoDock 4.2 softwareusing the program O. Mutations in exon 19 are the most common pathogenic mutations,so the crystal structures with these mutations are analyzed and compared in detail.In addition, we demonstrate how these crystal structures of EGFR conformationwith TK domain mutations and those binding with small molecule inhibitors unveilthe active or inactive mechanisms. As to the increasing resistance to the TKI,we summarize the progress on overcoming this challenge. Simultaneously, we predictthe structure of BIKW-2992 binding to EGFR and compare it with the validated structureof HKI-272. It is hoped that a more accurate resistance mechanism would be found.In brief, we believe that this research will provide insights into EGFR targetedtherapies.

Structural analysis of the EGFR TK domain and potential implications for EGFR targeted therapy