Skip to content
2000
Volume 21, Issue 4
  • ISSN: 1573-4099
  • E-ISSN: 1875-6697

Abstract

Background

The Computer-Aided Drug Discovery (CADD) approach was used to develop a few Epidermal Growth Factor Receptor (EGFR) kinase inhibitors. EGFR kinase expression is highly associated with genomic instability, higher proliferation, lower hormone receptor levels, and HER2 over-expression. It is more common in breast cancer. Thus, EGFR Kinase is one of the main targets in discovering new cancer medicine.

Objectives

To computationally validate some amides substituted β-amino enones as EGFR inhibitors and to carry out associated anticancer agents.

Methods

We used tools such as molecular docking, MD simulations, DFT calculations, and ADMET predictions to establish a preliminary SAR. we used BT474 (ER+HER2+) and MCF-7 (ER-HER2) cell lines along with normal breast cell epithelial cells (MFC-10a) for anticancer studies and EGFR kinase inhibition assay studies. As the Reactive Oxygen Species (ROS) plays the main role in cancer development, we also analyzed the antioxidant potentials of these compounds.

Results

Among the family of eleven amides substituted (Z)-β-amino enones (), compounds , , , and showed valuable and bio-activity. Remarkably, the results almost coincided with study results.

Conclusion

We recommend compounds , , , and for pre-clinical and clinical evaluation to establish them as future cancer therapeutics.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cad/10.2174/0115734099266822231219073332
2024-01-30
2025-09-04

  • From This Site

    /content/journals/cad/10.2174/0115734099266822231219073332
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. SubramaniamP. RamasubbuC. AthiramuS. Exploiting intramolecular hydrogen bonding for the highly (Z)-selective & metal free synthesis of amide substituted β-aminoenones.Green Chem.201719112541254510.1039/C7GC00909G
     [Google Scholar]
  2. CueB.W. ZhangJ. Green process chemistry in the pharmaceutical industry.Green Chem. Lett. Rev.20092419321110.1080/17518250903258150
     [Google Scholar]
  3. BryanM.C. DiorazioL. FeiZ. FraunhofferK. HaylerJ. HickeyM. HughesS. HumphreysL. RichardsonP. SchoberM. StevenA. WhiteT. WuytsS. YinJ. Green chemistry articles of interest to the pharmaceutical industry.Org. Process Res. Dev.201721215316410.1021/acs.oprd.7b00014
     [Google Scholar]
  4. TuckerJ.L. FaulM.M. Industrial research: Drug companies must adopt green chemistry.Nature20165347605272910.1038/534027a27251259
     [Google Scholar]
  5. de MartelC. GeorgesD. BrayF. FerlayJ. CliffordG.M. Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis.Lancet Glob. Health202082e180e19010.1016/S2214‑109X(19)30488‑731862245
     [Google Scholar]
  6. ZugazagoitiaJ. GuedesC. PonceS. FerrerI. Molina-PineloS. Paz-AresL. Current challenges in cancer treatment.Clin. Ther.20163871551156610.1016/j.clinthera.2016.03.02627158009
     [Google Scholar]
  7. SambiM. BagheriL. SzewczukM.R. Current challenges in cancer immunotherapy: Multimodal approaches to improve efficacy and patient response rates.J. Oncol.2019201911210.1155/2019/450879430941175
     [Google Scholar]
  8. SubramamiamP. RamasubbuC. AthiramuS. ArumugamS. AlagumuthuM. Pharmacological explorations of eco-friendly amide substituted (Z)-β-enaminones as anti-breast cancer drugs.Arch. Pharm.20193521e180024430515835
     [Google Scholar]
  9. FischerJ. GanellinC.R. Analogue-based Drug Discovery.John Wiley & Sons200651110.1002/3527608001
     [Google Scholar]
  10. DamarajuV.L. DamarajuS. YoungJ.D. BaldwinS.A. MackeyJ. SawyerM.B. CassC.E. Nucleoside anticancer drugs: The role of nucleoside transporters in resistance to cancer chemotherapy.Oncogene200322477524753610.1038/sj.onc.120695214576856
     [Google Scholar]
  11. Seley-RadtkeK.L. YatesM.K. The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold.Antiviral Res.2018154668610.1016/j.antiviral.2018.04.00429649496
     [Google Scholar]
  12. PérigaudC. GosselinG. ImbachJ.L. Nucleoside analogs as chemotherapeutic agents: A review.Nucleosides Nucleotides1992112-490394510.1080/07328319208021748
     [Google Scholar]
  13. ParkerW.B. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer.Chem. Rev.200910972880289310.1021/cr900028p19476376
     [Google Scholar]
  14. SauterB. GillinghamD. Profiling the nucleobase and structure selectivity of anticancer drugs and other DNA alkylating agents by RNA sequencing.ChemBioChem201819151638164210.1002/cbic.20180023529732707
     [Google Scholar]
  15. SimenelA.A. MorozovaE.A. SnegurL.V. ZykovaS.I. KachalaV.V. OstrovskayaL.A. BluchterovaN.V. FominaM.M. Simple route to ferrocenylalkyl nucleobases. Antitumor activity in vivo.Appl. Organomet. Chem.200923621922410.1002/aoc.1500
     [Google Scholar]
  16. DhorajiyaB.D. IbrahimA.S. BadriaF.A. DholakiyaB.Z. Design and synthesis of novel nucleobase-based barbiturate derivatives as potential anticancer agents.Med. Chem. Res.201423283984710.1007/s00044‑013‑0683‑4
     [Google Scholar]
  17. ZhilinaZ.V. GumenyukV.V. NekrasovY.S. BabinV.N. SnegurL.V. StarikovaZ.A. YanovskyA.I. Structures of ferrocenylalkyl derivatives of adenine.Russ. Chem. Bull.19984791781178410.1007/BF02495705
     [Google Scholar]
  18. ZahedipourF. DalirfardoueiR. KarimiG. JamialahmadiK. Molecular mechanisms of anticancer effects of Glucosamine.Biomed. Pharmacother.2017951051105810.1016/j.biopha.2017.08.12228922722
     [Google Scholar]
  19. ReginsterJ.Y. DeroisyR. RovatiL.C. LeeR.L. LejeuneE. BruyereO. GiacovelliG. HenrotinY. DacreJ.E. GossettC. Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomised, placebo-controlled clinical trial.Lancet2001357925225125610.1016/S0140‑6736(00)03610‑211214126
     [Google Scholar]
  20. ZhuX. SangL. WuD. RongJ. JiangL. Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: A meta-analysis of randomized controlled trials.J. Orthop. Surg. Res.201813117010.1186/s13018‑018‑0871‑529980200
     [Google Scholar]
  21. EraslanA. UlkarB. Glucosamine supplementation after anterior cruciate ligament reconstruction in athletes: A randomized placebo-controlled trial.Res. Sports Med.2015231142610.1080/15438627.2014.97580925630243
     [Google Scholar]
  22. ChesnokovV. GongB. SunC. ItakuraK. Anti-cancer activity of glucosamine through inhibition of N-linked glycosylation.Cancer Cell Int.20141414510.1186/1475‑2867‑14‑4524932134
     [Google Scholar]
  23. SudhapriyaN. ManikandanA. KumarM.R. PerumalP.T. Cu-mediated synthesis of differentially substituted diazepines as AChE inhibitors; validation through molecular docking and Lipinski’s filter to develop novel anti-neurodegenerative drugs.Bioorg. Med. Chem. Lett.201929111308131210.1016/j.bmcl.2019.04.00230956014
     [Google Scholar]
  24. AlagumuthuM. MuralidharanV.P. AndrewM. AhmedM.H. IyerS.K. ArumugamS. Computational approaches to develop isoquinoline based antibiotics through DNA gyrase inhibition mechanisms unveiled through antibacterial evaluation and molecular docking.Mol. Inform.20183712180004810.1002/minf.20180004830051592
     [Google Scholar]
  25. AlagumuthuM. ArumugamS. Molecular docking, discovery, synthesis, and pharmacological properties of new 6-substituted-2-(3-phenoxyphenyl)-4-phenyl quinoline derivatives; an approach to developing potent DNA gyrase inhibitors/antibacterial agents.Bioorg. Med. Chem.20172541448145510.1016/j.bmc.2017.01.00728094220
     [Google Scholar]
  26. KurupS. McAllisterB. LiskovaP. MistryT. FanizzaA. StanfordD. SlawskaJ. KellerU. HoelleinA. Design, synthesis and biological activity of N 4 -phenylsubstituted-7 H -pyrrolo[2,3- d ]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase.J. Enzyme Inhib. Med. Chem.2018331748410.1080/14756366.2017.137666629115879
     [Google Scholar]
  27. ZegzoutiH. ZdanovskaiaM. HsiaoK. GoueliS.A. ADP-Glo: A Bioluminescent and homogeneous ADP monitoring assay for kinases.Assay Drug Dev. Technol.20097656057210.1089/adt.2009.022220105026
     [Google Scholar]
  28. KumarM.R. ManikandanA. SivakumarA. DhayabaranV.V. An eco-friendly catalytic system for multicomponent, one-pot synthesis of novel spiro-chromeno indoline-triones and their anti-prostate cancer potentials evaluated via alkaline phosphatase inhibition mechanism.Bioorg. Chem.201881445410.1016/j.bioorg.2018.07.03730118985
     [Google Scholar]
  29. ThangarasuP. Thamarai SelviS. ManikandanA. Unveiling novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl)quinolines as GPCR ligands via PI3-kinase/PAR-1 antagonism and platelet aggregation valuations; development of a new class of anticancer drugs with thrombolytic effects.Bioorg. Chem.20188146848010.1016/j.bioorg.2018.09.01130243238
     [Google Scholar]
  30. BinduB. VijayalakshmiS. ManikandanA. Discovery, synthesis and molecular substantiation of N-(benzo[d]thiazol-2-yl)-2-hydroxyquinoline-4-carboxamides as anticancer agents.Bioorg. Chem.20199110317110.1016/j.bioorg.2019.10317131382059
     [Google Scholar]
  31. MuralidharanV.P. AlagumuthuM. ArumugamS. IyerS.K. Molecular substantiation and drug efficacy of relatively high molecular weight S‐BINOLs; Appraised as breast cancer medication and PI3Kinase inhibitors.J. Heterocycl. Chem.20185561339134510.1002/jhet.3166
     [Google Scholar]
  32. RajeshK.M. ManikandanA. VioletD.V. N-substituted Hydroxynaphthalene imino-oxindole derivatives as a new class of pi3-kinase inhibitor and breast cancer drug: Molecular validation and SAR studies.Chem. Biol. Drug Des.201891127728410.1111/cbdd.1307928791774
     [Google Scholar]
  33. ManikandanA. SivakumarA. NigamP.S. NapoleonA.A. Anticancer effects of novel tetrahydro-dimethyl-xanthene-diones.Anticancer. Agents Med. Chem.202020790991610.2174/187152062066620031809413832188389
     [Google Scholar]
  34. ManikandanA. MoharilP. SathishkumarM. Muñoz-GarayC. SivakumarA. Therapeutic investigations of novel indoxyl-based indolines: A drug target validation and Structure-Activity Relationship of angiotensin-converting enzyme inhibitors with cardiovascular regulation and thrombolytic potential.Eur. J. Med. Chem.201714141742610.1016/j.ejmech.2017.09.07629032034
     [Google Scholar]
  35. EcclesS.A. The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology.Int. J. Dev. Biol.2011557-8-968569610.1387/ijdb.113396se22161825
     [Google Scholar]
  36. DownwardJ. YardenY. MayesE. ScraceG. TottyN. StockwellP. UllrichA. SchlessingerJ. WaterfieldM.D. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences.Nature1984307595152152710.1038/307521a06320011
     [Google Scholar]
  37. SchulzeW.X. DengL. MannM. Phosphotyrosine interactome of the ErbB‐receptor kinase family.Mol. Syst. Biol.2005112005.000810.1038/msb410001216729043
     [Google Scholar]
  38. SigismundS. AvanzatoD. LanzettiL. Emerging functions of the EGFR in cancer.Mol. Oncol.201812132010.1002/1878‑0261.1215529124875
     [Google Scholar]
  39. ChenJ.F. YanQ. The roles of epigenetics in cancer progression and metastasis.Biochem. J.2021478173373339310.1042/BCJ2021008434520519
     [Google Scholar]
  40. GonzalezH. HagerlingC. WerbZ. Roles of the immune system in cancer: From tumor initiation to metastatic progression.Genes Dev.20183219-201267128410.1101/gad.314617.11830275043
     [Google Scholar]
  41. TopalianS.L. DrakeC.G. PardollD.M. Immune checkpoint blockade: A common denominator approach to cancer therapy.Cancer Cell201527445046110.1016/j.ccell.2015.03.00125858804
     [Google Scholar]
  42. SynN.L. TengM.W.L. MokT.S.K. SooR.A. De-novo and acquired resistance to immune checkpoint targeting.Lancet Oncol.20171812e731e74110.1016/S1470‑2045(17)30607‑129208439
     [Google Scholar]
  43. KähkönenT.E. HalleenJ.M. BernoulliJ. Immunotherapies and metastatic cancers: Understanding utility and predictivity of human immune cell engrafted mice in preclinical drug development.Cancers2020126161510.3390/cancers1206161532570871
     [Google Scholar]
  44. WaldmanA.D. FritzJ.M. LenardoM.J. A guide to cancer immunotherapy: From T cell basic science to clinical practice.Nat. Rev. Immunol.2020201165166810.1038/s41577‑020‑0306‑532433532
     [Google Scholar]
  45. ThomasR. WeihuaZ. Rethink of EGFR in cancer with is kinase-independent function on board.Front. Oncol.2019980010.3389/fonc.2019.0080031508364
     [Google Scholar]
/content/journals/cad/10.2174/0115734099266822231219073332
Loading
EGFR Kinase Inhibiting Amino-enones for Breast Cancer; CADD Approach
Curr. Computeraided Drug Des. 21, 549 (2025); https://doi.org/10.2174/0115734099266822231219073332
/content/journals/cad/10.2174/0115734099266822231219073332
/content/journals/cad/10.2174/0115734099266822231219073332
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): ADMET; anticancer; breast cancer; CADD; EGFR kinase; molecular docking

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test