Recent development of heterocyclic scaffolds as EGFR kinase inhibitors in cancer
DOI:
https://doi.org/10.12923/cipms-2025-0018Keywords:
cancer, heterocyclic scaffolds, kinase inhibitorsAbstract
The Epidermal Growth Factor Receptor (EGFR) is responsible for cell differentiation and proliferation upon activation when it binds to one of its ligands. It is thought to be involved tumorigenesis, which is implicated in cancers such as lung cancer and breast cancer. Over the past decades, the EGFR has become extensively examined as a target for the development of new anticancer agents. Several EGFR tyrosine kinase inhibitors (TKIs) have been identified and assessed in clinical trials as potential treatments for carcinoma. This review provides updated information on Novel heterocyclic scaffolds, which are now considered important pharmacophores that have demonstrated significant potency as EGFR inhibitors. Kinase inhibitors, in the last few years, have emerged as emerging anticancer agents with promising results. In this review, we briefly discussed heterocyclic scaffolds and the structural activity relationships of lead compounds such as substituted quinazoline, pyrimidine, quinoline and indole as EGFR kinase inhibitors, as well as their use as anticancer agents. Information on miscellaneous heterocyclics such as thiazolyl-pyrazoline derivatives, pyrazole derivatives and oxadiazole derivatives is also included.
References
1. Global cancer facts and figures. ACS; 2021.
2. Guo Y, Pan W. ERK/MAPK signaling pathway and tumorigenesis. 2020; 1997-2007.
3. Trenkar R, Jura N. Recent tyrosine kinase activation: From the ligand perspective. Curr Opin Cell Biol. 2020;63:174-85.
4. Liang Y, Zhang T, Zhang J. Natural tyrosine kinase inhibitors acting on epidermal growth factor receptor: Their relevance for cancer therapy. Pharmacol Res. 2020;161:105164. https://doi.org/10.1016/j.phrs.2020.105164
5. Khan I, Zaib S. Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: an update on the development of synthetic methods and pharmacological diversification. Bioorg Med Chem. 2016;24:2361-81. https://doi.org/10.1016/j.bmc.2016.03.031
6. Bhatia P. Novel quinazoline-based EGFR kinase inhibitors: A review focussing on SAR and molecular docking studies (2015-2019). Euro J Med Chem. 2020;204:112640. https://doi.org/10.1016/j.ejmech.2020.112640
7. Rebuzzi S. Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: a review of the literature and future perspective. Crit Rev Oncol Hematol. 2020;146:102820. https://doi.org/10.1016/j.critrevonc.2019.102820
8. Das D. Recent advancements of 4-Aminoquinazoline derivatives as kinase inhibitors and their applications in medicinal chemistry. Euro J Med Chem. 2019;170:55-72. https://doi.org/10.1016/j.ejmech.2019.03.004
9. Qin X, Li Z, Yang L. Discovery of new [1, 4] dioxino [2, 3-f] quinazoline-based inhibitors of EGFR including the T790M/ L858R mutant. Bioorg Med Chem. 2016;24:2871-81.
10. Shao J, Chen E. 6- Oxazolidinequinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR. Bioorg Med Chem. 2016;24:3359-70.
11. Cheng W, Zhu S. Design, synthesis and biological evaluation of 6-(nitroimidazole-1H-alkyloxyl)-4- anilinoquinazolines as efficient EGFR inhibitors exerting cytotoxic effects both under normoxia and hypoxia. Eur J Med Chem. 2015;89:826-34. https://doi.org/10.1016/j.ejmech.2014.11.010
12. Zhang Y. Synthesis and in vitro biological evaluation of novel quinazoline derivatives. Bioorg Med Chem Lett. 2017;27:1584-7.
13. Chen L, Zhang Y, Liu J. Novel 4- arylaminoquinazoline derivatives with (E)-propen-1-yl moiety as potent EGFR inhibitors with enhanced antiproliferative activities against tumour cells. Eur J Med Chem. 2017;138:689-97. https://doi.org/10.1016/j.ejmech.2017.06.023
14. Zhang Y, Chen L, Xu H. 6, 7- Dimorpholinoalkoxy quinazoline derivatives as potent EGFR inhibitors with enhanced antiproliferative activities against tumour cells. Eur J Med Chem. 2018;147:77-89. https://doi.org/10.1016/j.ejmech.2018.01.090
15. Hou W, Ren Y, Zhang Z. Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors. Bioorg Med Chem. 2018;26:1740-50. https://doi.org/10.1016/j.bmc.2018.02.022
16. Zhang Y, Gao H. Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and alpha-glycosidase. Bioorg Med Chem Lett. 2017;27:4309-13.
17. Tu Y, Wang C. Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors. Bioorg Med Chem. 2017;25:3148-57. https://doi.org/10.1016/j.bmc.2017.04.001
18. Liu Z, Wang L, Feng M. New acrylamide-substituted quinazoline derivatives with enhanced potency for the treatment of EGFR T790M-mutant non-small-cell lung cancers. Bioorg Chem. 2018;77:593-9. https://doi.org/10.1016/j.bioorg.2018.01.035
19. Song J, Jang S, Lee J. Click chemistry for improvement in selectivity of quinazoline-based kinase inhibitors for mutant epidermal growth factor receptors. Bioorg Med Chem Lett. 2019;29:477-80. https://doi.org/10.1016/j.bmcl.2018.12.020
20. Das D, Xi L. Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities. Bioorg Med Chem Lett. 2019;29:591-6.
21. Tu Y, Wang C. Discovery of novel quinazoline derivatives bearing semicarbazone moiety as potent EGFR kinase inhibitors. Comput Struct Biotechnol J. 2018;16:462-78.
22. Hennequin LF. Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J Med Chem. 2002;45:1300-12. https://doi.org/10.1021/jm011022e
23. Qi H, Gong F. Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2. Euro J Medi Chem. 2017;125:245-54.
24. Mahdy H. Design, synthesis, molecular modelling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers. Bioorg Chem. 2020;94:103422. https://doi.org/10.1016/j.bioorg.2019.103422
25. Lee K, Jeong K. Pharmacophore modelling and virtual screening studies for new VEGFR-2 kinase inhibitors. Eur J Med Chem. 2010;45:5420-7.
26. Machado V , Peixoto D. Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3- [(thieno [3, 2-b] pyridin-7-ylthio) phenyl] ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors. Bioorg Med Chem. 2015;23:6497-509. https://doi.org/10.1016/j.bmc.2015.08.010
27. Wang Z, Wang N. ChenDietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signalling pathway. PLoS ONE. 2013;8:68566. https://doi.org/10.1371/journal.pone.0068566
28. Dietrich J, Hulme C. The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec®, Nexavar®, and BIRB-796. Bioorg Med Chem. 2010;8:5738-48. https://doi.org/10.1016/j.bmc.2010.05.063
29. Horne W, Yadav M. Heterocyclic peptide backbone modifications in a α-Helical Coiled Coil. J Am Chem Soc. 2004;126:15366-7. https://doi.org/10.1021/ja0450408
30. Reddy DM, Srinivas J. 4β-[(4-Alkyl)-1, 2, 3-triazol-1-yl] podophyllotoxins as anticancer compounds: Design, synthesis and biological evaluation. Eur J of Med Chem. 2011;46:1983-91. https://doi.org/10.1016/j.ejmech.2011.02.016
31. Banerji B, Chandrasekhar K. Synthesis of triazole-substituted quinazoline hybrids for anticancer activity and a lead compound as the EGFR blocker and ROS inducer agent. ACS Omega. 2018;3(11):16134-42. https://doi.org/10.1021/acsomega.8b01960
32. Liu J, Ming B. Current research on antibreast cancer synthetic compounds. RSC Adv. 2018;8:4386-416.
33. Zhu W, Zhai X, Fu Q. Design, synthesis and anticancer activity of 4-morpholinothieno [3, 2-d] pyrimidine derivatives bearing aryl methylene hydrazine moiety. Chem Pharm Bull. 2012;60:1037-45. https://doi.org/10.1248/cpb.c12-00342
34. Hamid M, Mihovilovic M. Synthesis of novel pyrazolo [3, 4-d] pyrimidine derivatives as potential anti-breast cancer agents. Eur J Med Chem. 2012;57:323-32. https://doi.org/10.1016/j.ejmech.2012.09.031
35. Omaima M, Hoda M. 2-Anilinopyrimidine derivatives: Design, synthesis, in vitro anti-proliferative activity, EGFR and ARO inhibitory activity, cell cycle analysis and molecular docking study. Bioorg Chem. 2020;99:103798. https://doi.org/10.1016/j.bioorg.2020.103798
36. Raymond E, Faivre S, Armand J. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 200;60:15-23. https://doi.org/10.2165/00003495-200060001-00002
37. Hemal A, Kini S. Synthesis, anticancer activity and docking of some substituted benzothiazoles as tyrosine kinase inhibitors. J Mol Graph Model. 2010;29(1):32-7. https://doi.org/10.1016/j.jmgm.2010.04.003
38. Elmetwally S. Design, synthesis and anticancer evaluation of thieno [2, 3-d] pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers. Bioorg Chem. 2019;88:102944. https://doi.org/10.1016/j.bioorg.2019.102944
39. Sharma V, Nandekar P. Structure guided design and binding analysis of EGFR inhibiting analogues of erlotinib and AEE788 using ensemble docking, molecular dynamics and MM-GBSA. RSC Adv. 2016;6:65725-35. https://doi.org/10.1039/c6ra08517b
40. Traxler P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Ther. 1999;82:195-206. https://doi.org/10.1016/s0163-7258(98)00044-8
41. Sequist LV, Piotrowska Z, Niederst MJ. Osimertinib responses after disease progression in patients who had been receiving rociletinib. JAMA Oncol. 2016;2:541-3. https://doi.org/10.1001/jamaoncol.2015.5009
42. Patel H, Ansari A. Design and synthesis of novel 2, 4-disubstituted aminopyrimidines: reversible non-covalent T790M EGFR inhibitors. J Recept Signal Transduct Res. 2018;38:393-412. https://doi.org/10.1080/10799893.2018.1557207
43. Elrazaz E, Serya R. Thieno [2, 3-d] pyrimidine-based derivatives as kinase inhibitor and anticancer agents. Future J Phar Sci. 2015;2:33-41. https://doi.org/10.1016/j.fjps.2015.09.001
44. Peng Y, Shiao H. Protein kinase inhibitor design by targeting the Asp-PheGly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J Med Chem. 2013;56:3889-903. https://doi.org/10.1021/jm400072p
45. Bugge S, Kaspersen S. Structure–activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor. Eur J Med Chem. 2014;75:354-74. https://doi.org/10.1016/j.ejmech.2014.01.042
46. Xu H. Discovery of N-substituted-3-phenyl-1, 6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2. Bioorg Med Chem. 2020;28:115555. https://doi.org/10.1016/j.bmc.2020.115555
47. Zhuo L. 2, 7-naphthyridinone-based MET kinase inhibitors: a promising novel scaffold for antitumor drug development. Eur J Med Chem. 2019;178:705-14.
48. Wang M. Synthesis and biological evaluation of new MET inhibitors with 1, 6-naphthyridinone scaffold. Eur J Med Chem. 2020;185:111803-16.
49. FischeR T. Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance. J Enzyme Inhib Med Chem. 2018;33:1-8. https://doi.org/10.1080/14756366.2018.1433261
50. Singh P. Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET. Bioorg Chem. 2018;79:163-70. https://doi.org/10.1016/j.bioorg.2018.04.001
51. Sever B. Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors. Eur J Med Chem. 2019;182:111648. https://doi.org/10.1016/j.ejmech.2019.111648
52. Ansari A. Review: biologically active pyrazole derivatives. New J Chem. 2017;41:16-41.
53. Chauhan M. Medicinal attributes of pyrazolo [3, 4-d] pyrimidines: a review. Bioorg Med Chem. 2013;21:5657-68.
54. Shukla P. Novel spiro/nonspiro pyranopyrazoles: eco-friendly synthesis, in-vitro anticancer activity, DNA binding, and in-silico docking studies. Curr Bioact Compound. 2019;15:257-67. https://doi.org/10.2174/1573407213666170828165512
55. Saleh N. Novel anticancer fused pyrazole derivatives as EGFR and VEGFR-2 dual TK inhibitors. Front Chem. 2020;7:917. https://doi.org/10.3389/fchem.2019.00917
56. Fathi M. 1, 3, 4-oxadiazole/chalcone hybrids: Design, synthesis, and inhibition of leukemia cell growth and EGFR, Src, IL-6 and STAT3 activities. Bioorg Chem. 2019;84:150-63. https://doi.org/10.1016/j.bioorg.2018.11.032
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Authors
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 Unported License.
