Overlap between EGFR ATP binding sites and Nelfinavir binding sites predicted by SMAP.Li XieThomas EvangelidisLei XiePhilip E. Bourne
we examined L834R-EGFR and T766M-EGFR (or L858R and T790M in numbering that include the 24 amino acids signal peptide). These two mutations are prevalent in non-small cell lung cancer (NSCLC) and located within exons 18–21 in the vicinity of the ATP-binding site (Fig.6a). L834R-m...
EGFR has three binding sites: an inactive site, a competitive ATP binding site, and an allosteric site. Ligands and drugs cannot bind the inactive site. Recent studies have mostly focused on either ATP-competitive inhibitors targeting the ATP binding site or molecules that bind the allosteric site...
The Y891 side-chain is some distance (>18 Å) away from erlotinib in the ATP-binding site of the wild-type EGFR TKD (Fig. 4a). Consistent with this, our kinase assays showed that the Y891D mutation does not substantially affect ATP binding (Table 2). In crystal structures of the...
3, 4 Targeted therapies such as TKI have been developed to target the EGFR ATP-binding site. Many previous clinical trials had suggested that for patients with advanced NSCLC with EGFR gene-sensitive mutations, the use of first generation EGFR-TKI gefitinib, erlotinib, ezetatinib, and second-...
The current EGFR TKIs all target the ATP- binding site; however, the C797S mutation blocks the covalent binding of these drugs, conferring resistance. EAI001 and EAI045 were rationally identified as a mol- ecule that binds allosterically to EGFR away from the binding site (non-ATP competitive...
The resistance to third-generation EGFR-TKIs caused by the trans-C797S mutation can be overcome by drugs targeting different kinase binding sites, including allosteric inhibitors, ATP-competitive inhibitors, and “dual-site” inhibitors that occupy both the ATP binding site and an allosteric site. ...
EGFR 受体以及激活和抗药性突变的位置。缩写:EGFR,表皮生长因子受体;ATP,三磷酸腺苷;TKI,酪氨酸激酶抑制剂。 文献十一、 EGFR基因的模块化结构和突变。EGFR 基因的结构显示在左侧,酪氨酸激酶 (TK) 域中突变的位置和类型显示在右侧。所有...
A cysteine (C797) located in the hinge region of the ATP binding site of EGFR was recently identified as a target of redox regulation21,22. Interestingly, a rise in H2O2 production was observed upon EGF binding25,26,27,28, which depended on a calcium-dependent H2O2 production by the ...
Subsequently, in order to validate whether these designed compounds can target EGFR, the molec- ular docking was performed by fitting these designed compounds and reference compound (Erlotinib) into the ATP binding site of EGFR. (PDB code: 1M17). Then, the obtained results have been plotted ...