Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jun 21;13(27):18825-18853.
doi: 10.1039/d3ra02347h. eCollection 2023 Jun 15.

Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review

Mostafa A Mansour  1 , Asmaa M AboulMagd  1 , Samar H Abbas  2 , Hamdy M Abdel-Rahman  3   4 , Mohamed Abdel-Aziz  2
Affiliations
Review

Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review

Mostafa A Mansour et al. RSC Adv. .

Abstract

Lung cancer is the second most common cause of morbidity and mortality among cancer types worldwide, with non-small cell lung cancer (NSCLC) representing the majority of most cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are among the most commonly used targeted therapy to treat NSCLC. Recent years have seen the evaluation of many synthetic EGFR TKIs, most of which showed therapeutic activity in pertinent models and were classified as first, second, and third-generation. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are ineffective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism. This review covers the fourth-generation EGFR-TKIs' most recent design with their essential binding interactions, the clinical difficulties, and the potential outcomes of treating patients with EGFR mutation C797S resistant to third-generation EGFR-TKIs was also discussed. Moreover, the utilization of various therapeutic strategies, including multi-targeting drugs and combination therapies, has also been reviewed.

PubMed Disclaimer

Conflict of interest statement

The authors affirm that they have no known financial or interpersonal conflicts that would have appeared to impact the research presented in this paper.

Figures

Fig. 1
Fig. 1. The EGFR structure, signaling pathways, and functions.
Fig. 2
Fig. 2. Wild-type EGFR bound to AMPPNP (PDB: 3VJO): (A) 3D binding mode of AMPPNP, receptor shown as hydrogen bond surface; (B) magnified 3D binding mode showing interactions with key residues; the figure was generated using BIOVIA Discovery Studio 2021.
Fig. 3
Fig. 3. EGFR TKIs' development timeline.
Fig. 4
Fig. 4. Representative molecules of 1st generation EGFR TKIs and their structural common features.
Fig. 5
Fig. 5. 2D interaction of gefitinib (1) at the EGFR TK binding site.
Fig. 6
Fig. 6. Representative molecules of 2nd generation EGFR TKIs and their common structural features.
Fig. 7
Fig. 7. 2D diagram of neratinib (6) at the binding site of mutant EGFRT790M TK.
Fig. 8
Fig. 8. Representative molecules of 3rd generation EGFR TKIs and their structural common features.
Fig. 9
Fig. 9. Overall view of the structure of EGFRL858R/T790M/C797S showed the ATP binding site in blue color and the allosteric binding site in green, the figure was generated using the crystal structure of mutant receptor (PDB ID: 6LUB) and BIOVIA Discovery Studio 2021.
Fig. 10
Fig. 10. Prototype allosteric EGFR TKIs and their common pharmcophoric features.
Fig. 11
Fig. 11. The optimization process of purine-based inhibitors 15, 16 using compound (14) as lead compound.
Fig. 12
Fig. 12. (A) 2D interactions of compound (14) with the active site of mutant EGFRL858R/T790M/C797S TK, (B) 2D interactions of compound (16) with active site of mutant EGFRL858R/T790M/C797S TK.
Fig. 13
Fig. 13. (A) Compound (17), (B) 2D interactions of compound (17) with active site of mutant EGFRL858R/T790M/C797S TK.
Fig. 14
Fig. 14. The amino pyrimidine compounds (18) and (19).
Fig. 15
Fig. 15. 2D diagram of compound (18) at the active site of mutated EGFR TK.
Fig. 16
Fig. 16. Optimization process for compound (21) from WZ4002 (20).
Fig. 17
Fig. 17. The optimization process of compounds (23–25) from compound (22) and their basic pharmacophore and binding residues.
Fig. 18
Fig. 18. 2D diagram of compound (25) at the binding site of mutant EGFRL858R/T790M/C797S TK.
Fig. 19
Fig. 19. (A) Compounds (26) and (27), (B) 2D interactions of compound (26) with active site of mutant EGFR TK.
Fig. 20
Fig. 20. Examples of pyrido[2,3-d]pyrimidine derivatives compounds (28) and (29).
Fig. 21
Fig. 21. The optimization process of compound (30) from the prototype lead compound EAI045 (13).
Fig. 22
Fig. 22. The optimization process of compound (32) via molecular hybridization.
Fig. 23
Fig. 23. The optimization process of quinazoline compounds (33–35).
Fig. 24
Fig. 24. Quinoline derivatives (36–38) as EGFRL858R/T790M/C797S TK inhibitors.
Fig. 25
Fig. 25. The optimization process of compound (39).
Fig. 26
Fig. 26. Common structural features of compounds (40) and (41).
Fig. 27
Fig. 27. The optimization process of compounds (43) and (44) from the lead compound (42).
Fig. 28
Fig. 28. 2D diagram of compound (44) at the binding site of the mutant EGFRL858R/T790M/C797S.
Fig. 29
Fig. 29. The optimization process of compounds (46) through rigidification of compound (45).
Fig. 30
Fig. 30. Spiro/aryl/phosphorous/oxygen compounds (47–49).
Fig. 31
Fig. 31. Marine alkaloid lamellarin N (50) and its modified analogue compound (51).
Fig. 32
Fig. 32. The optimization process of PROTAC compound (54).
Fig. 33
Fig. 33. (A) U-shape of 3rd generation EGFR TKIs WZ4002 (20) and osimertinib (8); (B) Y-shape of the non-ATP competitive inhibitors of mutant EGFRT790M EAI045 (13) and JBJ-04-125-02 (55).
Fig. 34
Fig. 34. Compounds (56–63) as examples of structures of EGFR inhibitors with Y-shaped configuration.
Fig. 35
Fig. 35. cis and trans of the T790M/C797S mutations.
Fig. 36
Fig. 36. Examples of multi-kinase inhibitors.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Warnakulasuriya S. Kujan O. Aguirre-Urizar J. M. Bagan J. V. González-Moles M. Á. Kerr A. R. Lodi G. Mello F. W. Monteiro L. Ogden G. R. Oral Dis. 2021;27:1862–1880. - PubMed
    1. Sain R. K. Chouhan R. Bagri L. P. Bajpa A. J. Cancer Res. Updates. 2012;1:129–152.
    1. Mahmood M. Q. Shukla S. D. Ward C. Walters E. H. Biomolecules. 2021;11:1394. - PMC - PubMed
    1. Lepucki A. Orlińska K. Mielczarek-Palacz A. Kabut J. Olczyk P. Komosińska-Vassev K. J. Clin. Med. 2022;11:1250. - PMC - PubMed
    1. Hoteit M. Oneissi Z. Reda R. Wakim F. Zaidan A. Farran M. Abi-Khalil E. El-Sibai M. Oncol. Lett. 2021;22:1–18. - PMC - PubMed