Structural analysis of the EGFR TK domain and potential implications             for EGFR targeted therapy.
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 domain             mutations, we aim at highlighting the current and future importance of these studies             on malignancies where the TK domain is improperly activated. The analysis is conducted             on published TK domain crystal structures deposited in the Protein Data Bank,             or homology structures generated by homology modeling and AutoDock 4.2 software             using 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 conformation             with TK domain mutations and those binding with small molecule inhibitors unveil             the active or inactive mechanisms. As to the increasing resistance to the TKI,             we summarize the progress on overcoming this challenge. Simultaneously, we predict             the structure of BIKW-2992 binding to EGFR and compare it with the validated structure             of 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 targeted             therapies.
Department of Medical Oncology, Jinling Hospital, Medical School                     of Nanjing University, Nanjing 210002, P.R. China.
Weiwei
W
Nie
Lin
L
Tang
Haiyang
H
Zhang
Jiaqing
J
Shao
Yucai
Y
Wang
Longbang
L
Chen
Donghai
D
Li
Xiaoxiang
X
Guan
D000077716:Afatinib; D000970:Antineoplastic Agents / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011799:Quinazolines / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry
D000970:Antineoplastic Agents; D011799:Quinazolines; D011804:Quinolines; D000077716:Afatinib; D066246:ErbB Receptors; C487932:neratinib