Zhao, Yan published the artcileRevisiting the molecular mechanism of acquired resistance to reversible tyrosine kinase inhibitors caused by EGFR gatekeeper T790M mutation in non-small-cell lung cancer, Related Products of indole-building-block, the publication is Medicinal Chemistry Research (2018), 27(9), 2160-2170, database is CAplus.
A variety of tyrosine kinase inhibitors (TKIs) have been developed to target human epidermal growth factor receptor (EGFR) for non-small-cell lung cancer (NSCLC) therapy. However, many patients treated with first-line TKIs are clin. observed to eventually establish a gatekeeper T790M mutation in EGFR active site, which plays a primary role in development of acquired resistance to TKIs. Here, we attempted to investigate the intermol. interactions of wild-type EGFR (EGFRWT) and its T790M mutant (EGFRT790M) with a number of culled reversible EGFR TKIs, paying attention to the structural and energetic response of inhibitor ligands to the mutation. A TKI panel consisting of 9 sophisticated EGFR inhibitors was manually culled, and an integration of structural modeling, virtual mutagenesis, quantum mechanics/mol. mechanics anal. and binding assay was performed to systematically examine the binding of these inhibitors to both wild-type and mutant EGFR. T790M-introduced steric hindrance plays a primary role in the acquired resistance to WT-selective inhibitors, whereas the mutation is observed to form addnl. noncovalent forces with WT-sparing inhibitors. Structural anal. reveals that the steric hindrance generally induces a conformational change of WT-selective inhibitors in EGFR active site, while the weak noncovalent forces have only a moderate effect on the binding mode of WT-sparing inhibitors. EAI045, the first fourth-generation EGFR inhibitor, exhibits a moderate affinity to EGFR and possesses an exquisite selectivity for wild type over mutant kinase (â?-fold). This is expected if considering that the EAI045 is an allosteric inhibitor, which does not need to directly compete with ATP, and high affinity and selectivity are therefore not required for the inhibitor.
Medicinal Chemistry Research published new progress about 1942114-09-1. 1942114-09-1 belongs to indole-building-block, auxiliary class Indoline,Thiazole,Fluoride,Amine,Benzene,Amide,Alcohol,Protein Tyrosine Kinase/RTK, name is 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, and the molecular formula is C9H9BN2O3, Related Products of indole-building-block.
Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles