Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR^{L858R/T790M/C797S})

Abstract

Tertiary EGFR C797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR L858R/T790M/C797S inhibitors. A representative compound, 8r-B, exhibited an IC 50 of 27.5 nM against the EGFR L858R/T790M/C797S mutant, while being a significantly less potent for EGFR WT (IC 50 > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

Hybrid Quinazoline 1,3,5‐Triazines as Epidermal Growth Factor Receptor (EGFR) Inhibitors with Anticancer Activity: Design, Synthesis, and Computational Study

“…As a result of intensive research, several EGFR inhibitors have been developed and are divided into generations based on their activity, for example, erlotinib (Tarceva®), [17] vandetanib (Caprelsa®), [19] gefitinib (Iressa®), [20] lapatinib (Tykerb®, Tyverb®), [21] and the current state of the art, osimertinib (Tagrisso®), [22] to name a few (Figure 2A). EGFR inhibitors can either be reversible or irreversible, with reversible inhibitors binding in the ATP binding pocket and irreversible inhibitors binding either to the Cys797 residue in the ATP binding pocket or to allosteric binding site(s) [23–26] …”

Rational Computational Design of Fourth-Generation EGFR Inhibitors to Combat Drug-Resistant Non-Small Cell Lung Cancer

“…Accordingly, the virtual screening and de novo design started with the preparation of a relevant structural model for the kinase domain of the d746-750/T790M/C797S mutant by homology modeling. The atomic coordinates of the target protein were produced using the active form of the L858R/T790M/C797S mutant as the structural template [28]. The optimized structural model for the d746-750/T790M/C797S mutant was validated with the ProSa 2003 program, which has been widely used as a valuable computational tool for examining whether the interactions of each amino-acid residue with the rest part of the protein are maintained favorably [32].…”

“…This two-track approach was intended to collect the putative inhibitors with binding free energies lower than -10 kcal/mol and higher than −6.0 kcal/mol with respect to the triple mutant and the wild type, respectively, which corresponds to at least 1000-fold difference in binding affinities. As a result that the bidentate hydrogen-bond interactions in the hinge region were characteristic of the effective fourth-generation EGFR inhibitors [27,28], only molecules capable of forming the two hydrogen bonds with backbone groups of residues 791-795 were selected with the distance criteria of <3.5 Å after all molecules in the docking library were screened.…”

“…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). This homology modeling began with the retrieval of the amino acid sequence of human EGFR comprising 1210 residues from UniProtKB protein knowledgebase (http://www.uniprot.org, accession number: P00533, gene name: EGFR ERBB).…”

“…The identification of L858R/T790M/C797S and d746-750/T790M/C797S mutant inhibitors has therefore been actively pursued to target the NSCLC cells resistant to the second-and the third-generation EGFR inhibitors. Although most triple mutant inhibitors were insufficient as a lead compound due to the higher biochemical potency against the wild type [24][25][26], some derivatives of 2-aryl-4-aminoquinazoline and 5-methylpyrimidopyridone proved to be good candidates for anti-NSCLC agent with high selectivity in the inhibition of the triple mutant [27,28]. The triple mutant inhibitors to suppress the resistance induced by C797S mutation are termed the fourth-generation EGFR inhibitors for which selectivity over the wild-type EGFR is also necessary to circumvent the severe potential side effects [29].…”