Insight into discovery of next generation reversible TMLR inhibitors targeting EGFR activating and drug resistant T790M mutants.

Insight into discovery of next generation reversible TMLR inhibitors targeting EGFR activating and drug resistant T790M mutants. Curr Cancer Drug Targets. 2017 Mar 30;: Authors: Agarwal SM, Pal D, Gupta M, Saini R Abstract Cancer is one of the most challenging diseases among the various causes of deaths worldwide. Among cancer, lung cancer rules as the leading cause of cancer-related deaths annually.The majority of the lung cancers identified are non-small cell lung cancer (NSCLC). Clinically, the Epidermal Growth Factor Receptor (EGFR) is a therapeutically accepted target for NSCLC. Many therapeutic leads that target this transmembrane receptor protein were tested for anti-EGFR activity that led to the discovery of gefitinib and erlotinib. These ATP-competitive first generation EGFR inhibitors are the first-line treatment of EGFR-mutated lung cancer. Though, these have proven highly effective against EGFR activating mutants, but their inefficacy was noticed shortly after the treatment due to an acquired secondary mutation (T790M). Clinical studies demonstrated that this mutation alters the binding site which makes first generation inhibitors ineffective. Henceforth, second and third generation inhibitors emerged having covalent and irreversible mode of action. Second generation inhibitors like afatinib and dacomitinib exhibit inhibitory activity for both wtEGFR and EGFR T790M, while the third generation inhibitors like osimertinib a...
Source: Current Cancer Drug Targets - Category: Cancer & Oncology Authors: Tags: Curr Cancer Drug Targets Source Type: research