Abstract
Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants with drug resistance. It has thus become urgent to identify potent and selective inhibitors of triple mutant EGFRs resistant to first-, second-, and third-generation EGFR inhibitors. Herein, we report the discovery of potent and highly selective inhibitors of EGFR exon 19 p.E746_A750del/EGFR exon 20 p.T790M/EGFR exon 20 p.C797S (d746-750/T790M/C797S) mutant, which were derived via two-track virtual screening and de novo design. This two-track approach was performed so as to maximize and minimize the inhibitory activity against the triple mutant and the wild type, respectively. Extensive chemical modifications of the initial hit compounds led to the identification of several low-nanomolar inhibitors of the d746-750/T790M/C797S mutant. Among them, two compounds exhibited more than 104-fold selectivity in the inhibition of EGFRd746-750/T790M/C797S over the wild type. The formations of a hydrogen bond with the mutated residue Ser797 and the van der Waals contact with the mutated residue Met790 were found to be a common feature in the interactions between EGFRd746-750/T790M/C797S and the fourth-generation inhibitors. Such an exceptionally high selectivity could also be attributed to the formation of the hydrophobic contact with a Gly loop residue or the hydrogen bond with Asp855 in the activation loop. The discovery of the potent and selective EGFRd746-750/T790M/C797S inhibitors were actually made possible by virtue of the modified protein–ligand binding free energy function involving a new hydration free energy term with enhanced accuracy. The fourth-generation EGFR inhibitors found in this work are anticipated to serve as a new starting point for the discovery of anti-NSCLC medicines to overcome the problematic drug resistance.
Highlights
Epidermal growth factor receptor (EGFR) plays a key role in regulating various intracellular signaling for tumor cell proliferation, differentiation, migration, and invasion [1,2]
As a result that the 3D structure of d746-750/T790M/C797S mutant EGFR was unavailable in Protein Data Bank (PDB), its atomic coordinates were constructed by homology modeling using the active conformation of the L858R/T790M/C797S mutant [28] as the structural template (PDB entry: 6JRJ)
Based on the two-track virtual screening and the targeted de novo design, we discovered the effective fourth-generation EGFR inhibitors highly selective for the d746-750/T790M/C797S mutant over the wild type
Summary
Epidermal growth factor receptor (EGFR) plays a key role in regulating various intracellular signaling for tumor cell proliferation, differentiation, migration, and invasion [1,2]. The most constitutively activating mutations include the L858R single point mutation and the deletion of Glu746-Ala750 (d746-750) [6,7] In this regard, it has served as a good therapeutic treatment of NSCLC to impair the kinase activity of the oncogenic mutants with first-generation EGFR inhibitors [8,9,10,11]. Targeting the L858R and d746-750 mutants by the first-generation EGFR inhibitors became problematic with the manifestation of drug resistance in NSCLC patients This acquired resistance was due to a secondary somatic mutation (T790M) in the hinge region [12,13,14,15], which caused the increase in the steric repulsions with the first-generation inhibitor drugs. A great deal of efforts has been devoted to the discovery of the new EGFR inhibitors specific for the drug-resistant d746-750/T790M and L8585R/T790M double mutants [17,18,19], which was characteristic of the third-generation inhibitors
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