Design and synthesis of the novel, selective WZ4002 analogue as EGFR-L858R/T790M tyrosine kinase inhibitors for targeted drug therapy in non-small-cell lung cancer (NSCLC)

To conquer the drug-resistance of first-generation EGFR (epidermal growth factor receptor) kinase inhibitors and second-generation inhibitors' non-selective toxicities in Non-Small Cell Lung Cancer (NSCLC) patients, a series of WZ4002 derivatives (6-46) were discovered as novel double mutant EGFR-L858R/T790M TK inhibitors. This objective was attained by employing structure-based drug design and traditional optimization strategies based on the WZ4002 scaffold. Among the synthesized compounds, representative compounds 8 and 38 displayed significant anti-proliferative activity on the Gefitinib-resistant cell line NCI-H1975, with an IC50 value of 0.179 mu M and 0.173 mu M, respectively. Also, these compounds exhibited moderate anti-proliferative activity against the A549 cell, with an IC50 of 0.550 mu M and 0.528 mu M respectively, suggesting their improved selectivity over the mutant EGFR-L858R/T790M. Excitingly, both these compounds showed significant inhibition of the double mutant EGFR-L858R/T790M TK with an IC50 value of 0.0063 mu M and 0.0060 mu M, respectively. The IC50 values of both the promising compounds against the HepG2 cell line were more than 1 mu M, indicating safety for normal cells. Covalent docking and MD simulation further confirm their irreversible binding mode with the target protein. These results demonstrate that compounds 8 and 38 would be promising lead compound-targeting double mutant EGFR-L858R/T790M TK. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

A series of novel double mutant EGFR-L858R/T790M TK inhibitors were discovered using structure-based drug design and traditional optimization strategies. These inhibitors showed improved selectivity and lower toxicity, making them promising candidates for targeting the double mutant EGFR-L858R/T790M TK.