Journal article

Mechanistic Study of Potent Fluorinated EGFR Kinase Inhibitors with a Quinazoline Scaffold against L858R/T790M/C797S Resistance Mutation: Unveiling the Fluorine Substituent Cooperativity Effect on the Inhibitory Activity

Research Areas

Currently no objects available

Publication Details

Author list: Akher Farideh Badichi, Farrokhzadeh Abdolkarim, Ravenscroft Neil, Kuttel Michelle M.

Publisher: American Chemical Society

Publication year: 2020

Journal: Journal of Physical Chemistry B

Volume number: 124

Issue number: 28

Start page: 5813

End page: 5824

Total number of pages: 12

ISSN: 1520-6106

eISSN: 1520-5207



Fluorination has considerable potential with regards to the design of kinase inhibitors for anti-carcinoma therapy. It was recently reported that fluorination increases the potency of inhibitors of the epidermal growth factor receptor (EGFR) – mutations of which have been linked specifically to non-small-cell lung cancer. For the L858R/T790M/C797S triplet mutant (EGFRTM) a trifluorinated inhibitor, 25g, was found to have 4.23 times greater potency against EGFRTM than a monofluorinated inhibitor, 25a. This discovery necessitates a rational explanation for the underlying inhibitory mechanisms. Here we apply multiple computational approaches to explore, validate, and differentiate the binding modes of 25a and 25g in EGFRTM and to investigate the additive effects of fluorine substitution on the inhibitory activity. Our results showed that EGFRTM in the presence of 25g undergoes a series of conformational changes that favor inhibitor binding to both the active and allosteric sites. Further, the additivity of fluorine substitution is positive: the complex stability is increased by each additional fluorine substituent. Estimated binding free energies show good correlation with the experimental biological activity, with van der Waals interactions the principal contributor to variations in the binding affinities of 25a and 25g to EGFRTM. Per-residue energy-based hierarchical clustering analysis suggests that three hot-spot residues — L718, K745 and D855 — are key in achieving optimal binding modes for 25g with higher affinity in EGFRTM compared to 25a. This study provides a rationale for the superior EGFRTM-inhibitory potency exhibited by 25g over 25a. which is expected to be useful for future rational structure-based design of novel EGFRTM inhibitors with improved potency and selectivity.


Currently no objects available


Currently no objects available

Last updated on 2021-22-01 at 17:18