Skip to content
2000
Volume 20, Issue 4
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM.

Objective

In this research, the objective was to perform structure-based screening with the aim of identifying natural compounds proficient in targeting the DNA-binding domain (DBD) of the FOXM1 protein.

Methods

In this study, tools were employed to screen a hundred naturally occurring compounds capable of targeting the FOXM1 protein. Through molecular docking analysis and pharmacokinetic profiling, five compounds were promising candidates for extensive interaction with the FOXM1 protein. Further, these compounds were validated for the stability of the FOXM1-natural compound complex using molecular dynamics (MD) simulations.

Results

Four compounds, such as Withaferin A, Bryophyllin A, Silybin B, Sanguinarine and Troglitazone (control compound), emerged as promising candidates with substantial interactions with FOXM1, suggesting their potential as a protein inhibitor based on molecular docking investigations. After MD simulation analysis, the FOXM1- Bryophyllin A complex was found to maintain the highest stability, and the other three ligands had moderate but comparable binding affinities over a period of 100 ns.

Conclusion

This study provides valuable insights into four promising FOXM1 inhibitors that can induce senescence in GBM stem cells. These findings contribute to developing structure-based designing strategies for FOXM1 inhibitors and innovative therapeutic approaches for treating Glioblastoma.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/pra/10.2174/0115748928289164240426110829
2025-05-09
2025-12-25

  • From This Site

    /content/journals/pra/10.2174/0115748928289164240426110829
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. PoonM.T.C. SudlowC.L.M. FigueroaJ.D. BrennanP.M. Longer-term (≥ 2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: A systematic review and meta-analysis.Sci. Rep.20201011162210.1038/s41598‑020‑68011‑432669604
     [Google Scholar]
  2. AlvesA.L.V. GomesI.N.F. CarloniA.C. RosaM.N. da SilvaL.S. EvangelistaA.F. ReisR.M. SilvaV.A.O. Role of glioblastoma stem cells in cancer therapeutic resistance: A perspective on antineoplastic agents from natural sources and chemical derivatives.Stem Cell Res. Ther.202112120610.1186/s13287‑021‑02231‑x33762015
     [Google Scholar]
  3. LeeY. KimK.H. KimD.G. ChoH.J. KimY. RheeyJ. ShinK. SeoY.J. ChoiY.S. LeeJ.I. LeeJ. JooK.M. NamD.H. FoxM1 promotes stemness and radio-resistance of glioblastoma by regulating the master stem cell regulator Sox2.PLoS One20151010e013770310.1371/journal.pone.013770326444992
     [Google Scholar]
  4. ManderK. Harford-WrightE. LewisK. VinkR. Advancing drug therapy for brain tumours: A current review of the pro-inflammatory peptide Substance P and its antagonists as anti-cancer agents.Recent Patents CNS Drug Discov.20149211012110.2174/157488980966614111114274025386916
     [Google Scholar]
  5. KatzenellenbogenB.S. GuillenV.S. KatzenellenbogenJ.A. Targeting the oncogenic transcription factor FOXM1 to improve outcomes in all subtypes of breast cancer.Breast Cancer Res.20232517610.1186/s13058‑023‑01675‑837370117
     [Google Scholar]
  6. HalasiM. GartelA.L. Targeting FOXM1 in cancer.Biochem. Pharmacol.201385564465210.1016/j.bcp.2012.10.01323103567
     [Google Scholar]
  7. MengF.D. WeiJ.C. QuK. WangZ.X. WuQ.F. TaiM.H. LiuH.C. ZhangR.Y. LiuC. FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma.World J. Gastroenterol.201521119621310.3748/wjg.v21.i1.19625574092
     [Google Scholar]
  8. SuX. YangY. YangQ. PangB. SunS. WangY. QiaoQ. GuoC. LiuH. PangQ. NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma.BMC Cancer2021211118110.1186/s12885‑021‑08933‑y34740322
     [Google Scholar]
  9. MyattS.S. KongsemaM. ManC.W-Y. KellyD.J. GomesA.R. KhongkowP. KarunarathnaU. ZonaS. LangerJ.K. DunsbyC.W. CoombesR.C. FrenchP.M. BrosensJ.J. LamE.W-F. SUMOylation inhibits FOXM1 activity and delays mitotic transition.Oncogene201433344316432910.1038/onc.2013.54624362530
     [Google Scholar]
  10. MonteiroL.J. KhongkowP. KongsemaM. MorrisJ.R. ManC. WeekesD. KooC-Y. GomesA.R. PintoP.H. VargheseV. KennyL.M. Charles CoombesR. FreireR. MedemaR.H. LamE.W-F. The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment.Oncogene201332394634464510.1038/onc.2012.49123108394
     [Google Scholar]
  11. ShimJ.K. LimS.H. JeongJ.H. ChoiR.J. OhY. ParkJ. ChoiS. HongJ. KimS.J. MoonJ.H. KimE.H. TeoW.Y. ParkB.J. ChangJ.H. RyuJ.H. KangS.G. A lignan from Alnus japonica inhibits glioblastoma tumorspheres by suppression of FOXM1.Sci. Rep.20221211399010.1038/s41598‑022‑18185‑w35978012
     [Google Scholar]
  12. ZhangN. WeiP. GongA. ChiuW.T. LeeH.T. ColmanH. HuangH. XueJ. LiuM. WangY. SawayaR. XieK. YungW.K.A. MedemaR.H. HeX. HuangS. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis.Cancer Cell201120442744210.1016/j.ccr.2011.08.01622014570
     [Google Scholar]
  13. DaiB. KangS-H. GongW. LiuM. AldapeK.D. SawayaR. HuangS. Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells.Oncogene200726426212621910.1038/sj.onc.121044317404569
     [Google Scholar]
  14. LimS.V. RahmanM.B.A. TejoB.A. Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virusBMC bioinformatics, BioMed Central2011121311210.1186/1471‑2105‑12‑S13‑S24
     [Google Scholar]
  15. JaghooriM.M. BleijlevensB. OlabarriagaS.D. 1001 Ways to run AutoDock Vina for virtual screening.J. Comput. Aided Mol. Des.201630323724910.1007/s10822‑016‑9900‑926897747
     [Google Scholar]
  16. ManeP.T. WakureB.S. WakteP.S. Binary and ternary inclusion complexation of lapatinib ditosylate with β-cyclodextrin: Preparation, evaluation and in vitro anticancer activity.Beni. Suef Univ. J. Basic Appl. Sci.2022111117
     [Google Scholar]
  17. AlshehriS. ImamS.S. HussainA. AltamimiM.A. Formulation of piperine ternary inclusion complex using β CD and HPMC: physicochemical characterization, molecular docking, and antimicrobial testing.Processes2020811145010.3390/pr8111450
     [Google Scholar]
  18. PrasanthD.S.N.B.K. MurahariM. ChandramohanV. PandaS.P. AtmakuriL.R. GuntupalliC. In silico identification of potential inhibitors from Cinnamon against main protease and spike glycoprotein of SARS CoV-2.J. Biomol. Struct. Dyn.202139134618463210.1080/07391102.2020.177912932567989
     [Google Scholar]
  19. SharmaP. JoshiT. JoshiT. ChandraS. TamtaS. In silico screening of potential antidiabetic phytochemicals from Phyllanthus emblica against therapeutic targets of type 2 diabetes.J. Ethnopharmacol.202024811226810.1016/j.jep.2019.11226831593813
     [Google Scholar]
  20. MetwallyN.H. EldalyS.M. Design, synthesis of new pyrazoles and chromenes as ERK-2 inhibitors, apoptosis inducers and cell cycle interrupters based on thiophene-chalcone scaffold.ChemistrySelect2022745e20220225710.1002/slct.202202257
     [Google Scholar]
  21. SrivastavaR. TripathiS. UnniS. HussainA. HaqueS. DasguptaN. SinghV. MishraB.N. Silybin B and cianidanol inhibit Mpro and spike protein of SARS-CoV-2: Evidence from in silico molecular docking studies.Curr. Pharm. Des.202127323476348910.2174/138161282666620121012272633302853
     [Google Scholar]
  22. MehtaJ. UtkarshK. FuloriaS. SinghT. SekarM. SalariaD. RoltaR. BegumM.Y. GanS.H. RaniN.N.I.M. ChidambaramK. SubramaniyanV. SathasivamK.V. LumP.T. UthirapathyS. FadareO.A. AwofisayoO. FuloriaN.K. Antibacterial potential of Bacopa monnieri (L.) Wettst. and its bioactive molecules against uropathogens—an in silico study to identify potential lead molecule(s) for the development of new drugs to treat urinary tract infections.Molecules20222715497110.3390/molecules2715497135956923
     [Google Scholar]
  23. RachmaleM. RajputN. JadavT. SahuA.K. SharmaS. SenguptaP. High resolution mass spectrometry-driven metabolite profiling of baricitinib to report its unknown metabolites and step-by-step reaction mechanism of metabolism.Rapid Commun. Mass Spectrom.20223622e938510.1002/rcm.938536018833
     [Google Scholar]
  24. RoltaR. SalariaD. KumarV. PatelC.N. SourirajanA. BaumlerD.J. DevK. Molecular docking studies of phytocompounds of Rheum emodi Wall with proteins responsible for antibiotic resistance in bacterial and fungal pathogens: In silico approach to enhance the bio-availability of antibiotics.J. Biomol. Struct. Dyn.20224083789380310.1080/07391102.2020.185036433225862
     [Google Scholar]
  25. Vidal-LimonA. Aguilar-ToaláJ.E. LiceagaA.M. Integration of molecular docking analysis and molecular dynamics simulations for studying food proteins and bioactive peptides.J. Agric. Food Chem.202270493494310.1021/acs.jafc.1c0611034990125
     [Google Scholar]
  26. ZalaA.R. RajaniD.P. AhmadI. PatelH. KumariP. Synthesis, characterization, molecular dynamic simulation, and biological assessment of cinnamates linked to imidazole/benzimidazole as a CYP51 inhibitor.J. Biomol. Struct. Dyn.20234121115181153410.1080/07391102.2023.217091836691770
     [Google Scholar]
  27. KumarS. OhJ.M. AbdelgawadM.A. AbourehabM.A.S. TengliA.K. SinghA.K. AhmadI. PatelH. MathewB. KimH. Development of isopropyl-tailed chalcones as a new class of selective MAO-B inhibitors for the treatment of parkinson’s disorder.ACS Omega2023876908691710.1021/acsomega.2c0769436844523
     [Google Scholar]
  28. DesaiN.C. JadejaD.J. JethawaA.M. AhmadI. PatelH. DaveB.P. Design and synthesis of some novel hybrid molecules based on 4-thiazolidinone bearing pyridine-pyrazole scaffolds: Molecular docking and molecular dynamics simulations of its major constituent onto DNA gyrase inhibition.Mol. Divers.202311710.1007/s11030‑023‑10612‑y36750538
     [Google Scholar]
  29. SudevanS.T. OhJ.M. AbdelgawadM.A. AbourehabM.A.S. RangarajanT.M. KumarS. AhmadI. PatelH. KimH. MathewB. Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors.Sci. Rep.20221212240410.1038/s41598‑022‑26929‑x36575270
     [Google Scholar]
  30. KikiowoB. AhmadI. AladeA.A.T. IjatuyiT. IwaloyeO. PatelH.M. Molecular dynamics simulation and pharmacokinetics studies of ombuin and quercetin against human pancreatic α-amylase.J. Biomol. Struct. Dyn.20221810.1080/07391102.2022.215569936524470
     [Google Scholar]
  31. AljuhaniA. AhmedH.E.A. IhmaidS.K. OmarA.M. AlthagfanS.S. AlahmadiY.M. AhmadI. PatelH. AhmedS. AlmikhlafiM.A. El-AgrodyA.M. ZayedM.F. TurkistaniS.A. AbulkhairS.H. AlmaghrabiM. SalamaS.A. Al-KarmalawyA.A. AbulkhairH.S. In vitro and computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-M Pro inhibitors.RSC Advances20221241268952690710.1039/D2RA04015H36320844
     [Google Scholar]
  32. Tabatabaei-DakhiliS.A. Aguayo-OrtizR. DomínguezL. Velázquez-MartínezC.A. Untying the knot of transcription factor druggability: Molecular modeling study of FOXM1 inhibitors.J. Mol. Graph. Model.20188019721010.1016/j.jmgm.2018.01.00929414039
     [Google Scholar]
  33. ZhangZ. XueS. GaoY. LiY. ZhouZ. WangJ. LiZ. LiuZ. Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer.Cell Death Discov.20228128010.1038/s41420‑022‑01070‑w35680842
     [Google Scholar]
  34. XieZ.S. ZhouZ.Y. SunL.Q. YiH. XueS.T. LiZ.R. Structure-based virtual screening towards the discovery of novel FOXM1 inhibitors.Future Med. Chem.202214420721910.4155/fmc‑2021‑028234809496
     [Google Scholar]
  35. TangQ. RenL. LiuJ. LiW. ZhengX. WangJ. DuG. Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4-ATF3-CHOP axis.Cell Prolif.2020531e1270610.1111/cpr.1270631642559
     [Google Scholar]
  36. DhamiJ. ChangE. GambhirS.S. Withaferin A and its potential role in glioblastoma (GBM).J. Neurooncol.2017131220121110.1007/s11060‑016‑2303‑x27837436
     [Google Scholar]
  37. Hernández-CaballeroM.E. Sierra-RamírezJ.A. Villalobos-ValenciaR. Seseña-MéndezE. Potential of Kalanchoe pinnata as a cancer treatment adjuvant and an epigenetic regulator.Molecules20222719642510.3390/molecules2719642536234962
     [Google Scholar]
  38. NielsenA.H. OlsenC.E. MøllerB.L. Flavonoids in flowers of 16 Kalanchoë blossfeldiana varieties.Phytochemistry200566242829283510.1016/j.phytochem.2005.09.04116297414
     [Google Scholar]
  39. KambojA. SalujaA. Bryophyllum pinnatum (Lam.) Kurz.: Phytochemical and pharmacological profile: a review.Pharmacogn. Rev.200936364
     [Google Scholar]
  40. XuR. WuJ. LuoY. WangY. TianJ. TengW. ZhangB. FangZ. LiY. Sanguinarine represses the growth and metastasis of non-small cell lung cancer by facilitating ferroptosis.Curr. Pharm. Des.202228976076810.2174/138161282866622021712454235176976
     [Google Scholar]
  41. UllahA. AzizT. UllahN. NawazT. Molecular mechanisms of sanguinarine in cancer prevention and treatment.Anticancer. Agents Med. Chem.202323776577810.2174/187152062266622083112432136045531
     [Google Scholar]
  42. BiniendaA. ZiolkowskaS. PluciennikE. The anticancer properties of silibinin: Its molecular mechanism and therapeutic effect in breast cancer.Anticancer. Agents Med. Chem.202020151787179610.2174/187152062066619122014274131858905
     [Google Scholar]
  43. OsmaniyeaDerya AhmadIqrar LeventaBegüm Nurpelin Sağlık Serkan Design, synthesis and molecular docking and adme studies of novel hydrazone derivatives for ache inhibitory, bbb permeability and antioxidant effects.J Biomol Struct Dyn.202241189022903810.1080/07391102.2022.2139762
     [Google Scholar]
  44. HalderS.K. AhmadI. ShathiJ.F. MimM.M. HassanM.R. JewelM.J.I. DeyP. IslamM.S. PatelH. MorshedM.R. ShakilM.S. HossenM.S. A comprehensive study to unleash the putative inhibitors of serotype2 of dengue virus: insights from an in silico structure-based drug discovery.Mol. Biotechnol.202211410.1007/s12033‑022‑00582‑136307631
     [Google Scholar]
  45. AlsagabyS.A. IqbalD. AhmadI. PatelH. MirS.A. MadkhaliY.A. OyouniA.A.A. HawsawiY.M. AlhumaydhiF.A. AlshehriB. AlturaikiW. AlanaziB. MirM.A. Al AbdulmonemW. In silico investigations identified Butyl Xanalterate to competently target CK2α (CSNK2A1) for therapy of chronic lymphocytic leukemia.Sci. Rep.20221211764810.1038/s41598‑022‑21546‑036271116
     [Google Scholar]
  46. ÇevikU.A. CelikI. İnceU. MaryamZ. AhmadI. PatelH. ÖzkayY. KaplancıklZ.A. Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-thiadiazole derivatives as potent antimicrobial agents.Chem. Biodivers.202210.1002/cbdv.202201146
     [Google Scholar]
  47. AyipoY.O. AhmadI. AlananzehW. LawalA. PatelH. MordiM.N. Computational modelling of potential Zn-sensitive non-β-lactam inhibitors of imipenemase-1 (IMP-1).J. Biomol. Struct. Dyn.202212110.1080/07391102.2022.215316836476097
     [Google Scholar]
/content/journals/pra/10.2174/0115748928289164240426110829
Loading
Structure-Based Virtual Screening of Novel FOXM1 Inhibitors as Potential Compounds for Glioblastoma Treatment
Recent Patents on Anti-Cancer Drug Discovery 20, 558 (2025); https://doi.org/10.2174/0115748928289164240426110829
/content/journals/pra/10.2174/0115748928289164240426110829
/content/journals/pra/10.2174/0115748928289164240426110829
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): cancer stem cells (CSCs); Glioblastoma multiform (GBM); in silico; molecular docking; molecular dynamics simulation; phytochemical screening

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