Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations

The overexpression or mutation of the kinase domain of the epidermal growth factor receptor (EGFR) is strongly associated with non-small-cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) have proven to be effective in treating NSCLC patients. However, EGFR mutations can result in drug resistance. To elucidate the mechanisms underlying this resistance and inform future drug development, we examined the binding affinities of BLU-945, a recently reported fourth-generation TKI, to wild-type EGFR (EGFRWT) and its double-mutant (L858R/T790M; EGFRDM) and triple-mutant (L858R/T790M/C797S; EGFRTM) forms. We compared the binding affinities of BLU-945, BLU-945 analogues, CH7233163 (another fourth-generation TKI), and erlotinib (a first-generation TKI) using absolute binding free energy calculations. Our findings reveal that BLU-945 and CH7233163 exhibit binding affinities to both EGFRDM and EGFRTM stronger than those of erlotinib, corroborating experimental data. We identified K745 and T854 as the key residues in the binding of fourth-generation EGFR TKIs. Electrostatic forces were the predominant driving force for the binding of fourth-generation TKIs to EGFR mutants. Furthermore, we discovered that the incorporation of piperidinol and sulfone groups in BLU-945 substantially enhanced its binding capacity to EGFR TKIs.

 

Comments:

Your research sounds incredibly intricate and insightful! Studying the binding affinities of BLU-945 and its analogues to different forms of EGFR—wild-type and various mutant forms—is crucial for understanding drug resistance mechanisms in non-small-cell lung cancer (NSCLC) treatment.

Identifying key residues like K745 and T854 in the binding process sheds light on the specific interactions between fourth-generation EGFR TKIs and the receptor, offering a clearer picture of how these drugs work and potentially why they're effective against certain mutations.

The emphasis on electrostatic forces as the primary driving force for the binding of these fourth-generation TKIs to EGFR mutants is fascinating. It underscores the importance of considering molecular interactions beyond just chemical structure when designing effective drugs.

The enhancement of BLU-945's binding capacity through the incorporation of piperidinol and sulfone groups is a promising finding. Such modifications could potentially pave the way for more effective treatments by fine-tuning drug-receptor interactions.

Your work seems like a significant step forward in understanding drug resistance mechanisms and developing more potent therapies for NSCLC. What are your next steps based on these findings? Are there specific avenues for drug development or further research that your team is considering?

 

 

Related Products

Cat.No.	Product Name	Information
E1176	BLU-945	BLU-945 is a potent, highly selective, reversible and orally active epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKIs). BLU-945 can be used for the research of lung cancer including non-small cell lung cancer (NSCLC).

Related Targets

EGFR