Targeting EGFR^L858R/T790M and EGFR^{L858R/T790M/C797S} resistance mutations in NSCLC: Current developments in medicinal chemistry

Abstract

Both the first-generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second-generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib have significantly improved the survival of non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFR mutation leads to the clinically acquired resistance to the first- and second-generation EGFR-TKIs drugs. A number of the third-generation wild-type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFR . More recently, a tertiary EGFR mutation was reported as the dominant resistance mechanism to the third-generation irreversible inhibitors. It is highly desirable to develop the fourth-generation EGFR inhibitors. This review summarizes the mechanisms of acquired resistance and the latest medicinal chemistry advances on the third- and fourth-generation EGFR inhibitors, with special attention being paid to the allosteric and reversible inhibitors combating the tertiary EGFR mutation.

PI3K inhibitors: review and new strategies

“…93 Additional examples of such combinations are available. 94,95 The concept of allosteric drug working conjointly with an orthosteric drug is not new. We only need to consider that a 'ligand' can be an orthosteric drug, with the allosteric drug acting to modulate it.…”

Design, Synthesis and Biological Evaluation of the Quinazoline Derivatives as L858R/T790M/C797S Triple Mutant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

“…When R 1 was bromine, for aliphatic ring substitution of R 2 , it was found that compound with morpholinyl (22, 1.50 µM) had strong inhibition while piperidinyl (23) and piperazinyl (26) had no inhibition. For aromatic ring substitution of R 2 , compounds with phenyl (21) or pyridinyl (25) had no inhibition, while compounds of pyrimidinyl (20) and pyrazinyl (24) were active (0.44 and 0.69 µM, respectively). As can be seen, substituents R 2 had great influence on the inhibition of the triple mutant L858R/T790M/C797S EGFR tyrosine kinase.…”

“…The organic layer was separated and dried using anhydrous sodium sulfate, concentrated to afford a yellow solid 10.0 g, yield 66.8%, mp 116-118°C; 1 2-(5-Bromo-2-methoxyphenyl)-4-hydroxyquinazoline (3a): Intermediate 1 (20.0 g, 93.0 mmol) was dissolved in ethanol (60 mL), 2-aminobenzamide (12.7 g, 93.0 mmol) was added followed by iodine (26.0 g, 102 mmol). The reaction mixture stirred at reflux for 4 h. The reaction mixture was cooled to room temperature and quenched by 5% sodium thiosulfate solution, and extracted with dichloromethane for three times, the organic layer was separated and dried using anhydrous sodium sulfate, concentrated in vacuum, and the crude product was recrystallized from ethyl acetate to afford white solid 21 2-(5-Bromo-2-methoxyphenyl)-4-chloroquinazoline (4a): Com pound 3a (3.3 g, 10 mmol) was added to phosphorus oxychloride (10 mL), and then the reaction system was refluxed for 2 h, and then cooled to below 60°C. The phosphorus oxychloride was distilled under reduced pressure, and the mixture was cooled to room temperature.…”

“…However, the triple C797S mutation were observed in clinical treatment of patients carrying the EGFR T790M mutation, which impairs the formation of covalent bonds with the cysteine residue at position 797 of EGFR. 20,21) So far, there are no effective therapeutic strategies to overcome the L858R/T790M/C797S triple mutation of mediated EGFR-TKI resistance since the therapeutic antibody could not inhibit the expression of EGFR phosphorylated. Accordingly, it is particularly necessary to discovery novel EGFR inhibitors against the triple mutants involving C797S to overcome the resistance to third-generation drugs.…”

Receptor Tyrosine Kinase-Targeted Cancer Therapy

“…Moreover, a recent phase III study demonstrated that osimertinib was more effective as a first-line treatment compared to first-generation EGFR-TKIs in terms of PFS [ 115 ]. A recent study reported a tertiary C797S mutation as the cause of resistance to third-generation EGFR TKIs [ 116 ]. To overcome C797S, the development of fourth-generation EGFR inhibitors is highly desirable.…”