Next-generation EGFR tyrosine kinase inhibitors to overcome C797S mutation in non-small cell lung cancer (2019-2024)

Abstract

Lung cancer is a leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for the major portion (80-85%) of all lung cancer cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are commonly used as the targeted therapy for EGFR-mutated NSCLC. The FDA has approved first-, second- and third-generation EGFR-TKIs as therapeutics options. Osimertinib, the third-generation irreversible EGFR-TKI, has been approved for the treatment of NSCLC patients with the EGFR^T790M mutation. However, due to the EGFR^C797S mutation in the kinase domain of EGFR, resistance to osimertinib is observed and that limits the long-term effectiveness of the drug. The C797S mutation is one of the major causes of drug resistance against the third-generation EGFR TKIs. The C797S mutations including EGFR double mutations (19Del/C797S or L858R/C797S) and or EGFR triple mutations (19Del/T790M/C797S or L858R/T790M/C797S) cause major resistance to the third-generation EGFR-TKIs. Therefore, the discovery and development of fourth-generation EGFR-TKIs to target triple mutant EGFR with C797S mutation is a challenging topic in medicinal chemistry research. In this review, we discuss the discovery of novel fourth-generation EGFR TKIs, medicinal chemistry approaches and the strategies to overcome the C797S mutations. In vitro activities of EGFR-TKIs (2019-2024) against mutant EGFR TK, anti-proliferative activities, structural modifications, binding modes of the inhibitors and in vivo efficacies in animal models are discussed here.

Fig. 1. Schematic representation of the EGFR domains, exons and mutations in NSCLC.

Fig. 2. A schematic representation of the evolution of the 1st, 2nd, 3rd and 4th-generation EGFR TKIs against EGFR mutations, and the FDA approved drugs for NSCLC treatments.

Fig. 3. Chemical structure of CH7233163 and interactions of EGFR-^{L858R/T790M/C797S} (a cartoon diagram in light green) with CH7233163, blue-colour-coded stick model (PDB: 6LUB).

Fig. 4. Discovery of BLU-945 from hit at blueprint medicines and structure optimization sequence.

Fig. 5. Schematic representation of the discovery of BI-4020, fourth-generation active site binding EGFR inhibitor; interaction of BI-4020 with EGFR^{L858R/T790M/C797S} (PDB: 7KXZ).

Fig. 6. Brigatinib and other substituted pyrimidine-structures as 4th-generation EGFR-TKIs.

Fig. 7. Pyrimidine derivatives similar to the osimertinib structure.

Fig. 8. Osimertinib and brigatinib hydride structure and macrocycle 30; co-crystal structure of macrocycle 29 with EGFR^T790M/C797S (PDB: 7VRA).

Fig. 9. 4-Aminoquinazoline derivative from virtual screening.

Fig. 10. 4-Aminoquinazoline derivative via structure modification.

Fig. 11. EGFR TKIs via vandetanib core modification.

Fig. 12. JND3229 core modification and identification of compound 41.

Fig. 13. Pyrrolo[2,3-d]pyrimidine derivative as EGFR TKI.

Fig. 14. Substituted 9H-purine derivatives against triple mutant EGFR.

Fig. 15. Allosteric binding site inhibitors EAI001 & EAI005.

Fig. 16. Discovery of JBJ-09-063.

Fig. 17. Combination of allosteric binding and orthosteric binding sites.

Fig. 18. Diazopinone and quinazolinone scaffolds.

Fig. 19. Schematic representation of the PROTAC structures and the mechanism of action for target selective degradation.

Fig. 20. Some EGFR PROTACs based on first-, second-, and third-generation EGFR inhibitors.

Fig. 21. Some EGFR-PROTACs based on fourth-generation EGFR inhibitors targeting C797S mutation.

Fig. 22. (a) Crystal structure of EGFR^T790M in complex with osimertinib (PDB ID: 6JX4). (b) Crystal structure of EGFR^{L858R/T790M/C797S} in complex with osimertinib (PDB ID: 6LUD).

Fig. 23. Binding mode of brigatinib with EGFR^T790M/C797S (PDB ID: 8H7X).

Fig. 24. X-ray crystalline structure of JND3229 complexed with EGFR^T790M/C797S (PDB ID: 5ZTO).

Fig. 25. (a) EGFR kinase in complex with the allosteric inhibitor, EAI001 (PDB ID: 5D41); (b) EGFR^{T790M/C797S/V948R} in complex with EAI045 (PDB ID: 5ZWJ).