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Review
. 2024 Mar 23;29(7):1448.
doi: 10.3390/molecules29071448.

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy

Ya-Tao Wang  1 , Peng-Cheng Yang  2 , Jing-Yi Zhang  3 , Jin-Feng Sun  2
Affiliations
Review

Synthetic Routes and Clinical Application of Representative Small-Molecule EGFR Inhibitors for Cancer Therapy

Ya-Tao Wang et al. Molecules. .

Abstract

The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.

Keywords: EGFR; application; small molecule; synthetic routes; tyrosine kinase inhibitors (TKIs).

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Conflict of interest statement

The authors declared no financial interests.

Figures

Figure 1
Figure 1
Chemical structures of small-molecule EGFR inhibitors.
Figure 1
Figure 1
Chemical structures of small-molecule EGFR inhibitors.
Figure 2
Figure 2
EGFR signal pathway.
Scheme 1
Scheme 1
Synthesis of sunvozertinib.
Scheme 2
Scheme 2
Synthesis of mobocertinib succinate.
Scheme 3
Scheme 3
Synthesis of alflutinib.
Scheme 4
Scheme 4
Synthesis of lazertinib.
Scheme 5
Scheme 5
Synthesis of dacomitinib.
Scheme 6
Scheme 6
Synthesis of pyrotinib maleate.
Scheme 7
Scheme 7
Synthesis of neratinib.
Scheme 8
Scheme 8
Synthesis of brigatinib.
Scheme 9
Scheme 9
Synthesis of olmutinib.
Scheme 10
Scheme 10
Synthesis of osimertinib mesylate.
Scheme 11
Scheme 11
Synthesis of afatinib dimaleate.
Scheme 12
Scheme 12
Synthesis of vandetanib.
Scheme 13
Scheme 13
Synthesis of lapatinib ditosylate.
Scheme 14
Scheme 14
Synthesis of erlotinib hydrochloride.
Scheme 15
Scheme 15
Synthesis of gefitinib.
Scheme 16
Scheme 16
Synthesis of abivertinib.
Scheme 17
Scheme 17
Synthesis of poziotinib.
See this image and copyright information in PMC

References

    1. Yun C.H., Boggon T.J., Li Y., Woo M.S., Greulich H., Meyerson M., Eck M.J. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: Mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007;11:217–227. doi: 10.1016/j.ccr.2006.12.017. - DOI - PMC - PubMed
    1. Wood E.R., Truesdale A.T., McDonald O.B., Yuan D., Hassell A., Dickerson S.H., Ellis B., Pennisi C., Horne E., Lackey K., et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): Relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004;64:6652–6659. doi: 10.1158/0008-5472.CAN-04-1168. - DOI - PubMed
    1. Moyer J.D., Barbacci E.G., Iwata K.K., Arnold L., Boman B., Cunningham A., DiOrio C., Doty J., Morin M.J., Moyer M.P., et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 1997;57:4838–4848. - PubMed
    1. Louie G.V., Yang W., Bowman M.E., Choe S. Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor. Mol. Cell. 1997;1:67–78. doi: 10.1016/S1097-2765(00)80008-8. - DOI - PubMed
    1. Li D., Ambrogio L., Shimamura T., Kubo S., Takahashi M., Chirieac L.R., Padera R.F., Shapiro G.I., Baum A., Himmelsbach F., et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702–4711. doi: 10.1038/onc.2008.109. - DOI - PMC - PubMed