Skip to content
2000
Volume 25, Issue 10
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Cancer, characterized by aberrant cell growth, presents a formidable health challenge, impacting millions of individuals worldwide each year. Among the myriad mechanisms facilitating tumor progression, Vascular Endothelial Growth Factor receptors (VEGFR) play a pivotal role in driving angiogenesis the process by which tumors develop their own blood supply. This vascularization not only supports tumor nourishment and growth but also facilitates metastasis, enabling cancer to spread to distant sites. VEGFR inhibitors offer a strategic approach to disrupt the VEGF-VEGFR binding pathway, thereby impeding angiogenesis, metastasis, and the proliferation of cancer cells. This review elucidates the latest advancements in medicinal chemistry pertaining to VEGFR inhibitors, showcasing a variety of chemical moieties and assessing their efficacy across different cancer cell lines. The novel compounds highlighted in this review exhibit significant promise for anticancer evaluation through targeted VEGFR kinase inhibition. A robust body of , , and studies supports these findings, demonstrating the antitumor effects of these compounds. Computational analyses further enhance our understanding by predicting compound binding affinities, pharmacokinetics, and overall drug-likeness. Despite the significant progress made in developing effective VEGFR inhibitors, challenges remain in refining these agents for optimal cancer treatment. This review not only summarizes the advancements achieved in VEGFR inhibitor development but also emphasizes the ongoing hurdles that must be addressed to enhance the efficacy of cancer therapies.

Loading

Article metrics loading...

/content/journals/acamc/10.2174/0118715206356712241202112641
2025-01-10
2025-09-02
Loading full text...

Full text loading...

References

  1. RossiF. FredericksN. SnowdenA. AllegrezzaM.J. Moreno-NievesU.Y. Next generation natural killer cells for cancer immunotherapy.Front. Immunol.20221388642910.3389/fimmu.2022.88642935720306
    [Google Scholar]
  2. MoritzA. Cancer is not a disease!: It’s a survival mechanism: Discover cancer’s hidden purpose, heal its root causes, and be healthier than ever!Black stone2009
    [Google Scholar]
  3. StoneA. Living with Advanced Disease in a Canadian Cancer Hospital.Thesis, University of Toronto, 2016.2016
    [Google Scholar]
  4. AliE.S. SharkerS.M. IslamM.T. KhanI.N. ShawS. RahmanM.A. UddinS.J. ShillM.C. RehmanS. DasN. Targeting cancer cells with nanotherapeutics and nanodiagnostics: Current status and future perspectives.Seminars in cancer biology.Elsevier202169526810.1016/j.semcancer.2020.01.011
    [Google Scholar]
  5. MohammadR.M. MuqbilI. LoweL. YedjouC. HsuH-Y. LinL-T. SiegelinM.D. FimognariC. KumarN.B. DouQ.P. Broad targeting of resistance to apoptosis in cancer.Seminars in cancer biology.Elsevier2015Vol. 35S78S10310.1016/j.semcancer.2015.03.001
    [Google Scholar]
  6. AnandU. DeyA. ChandelA.K.S. SanyalR. MishraA. PandeyD.K. De FalcoV. UpadhyayA. KandimallaR. ChaudharyA. DhanjalJ.K. DewanjeeS. VallamkonduJ. Pérez de la LastraJ.M. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics.Genes Dis.20231041367140110.1016/j.gendis.2022.02.00737397557
    [Google Scholar]
  7. CordaniM. SomozaÁ. Targeting autophagy using metallic nanoparticles: a promising strategy for cancer treatment.Cell. Mol. Life Sci.20197671215124210.1007/s00018‑018‑2973‑y30483817
    [Google Scholar]
  8. ZhouB.B.S. ZhangH. DamelinM. GelesK.G. GrindleyJ.C. DirksP.B. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery.Nat. Rev. Drug Discov.200981080682310.1038/nrd213719794444
    [Google Scholar]
  9. DanceyJ.E. ChenH.X. Strategies for optimizing combinations of molecularly targeted anticancer agents.Nat. Rev. Drug Discov.20065864965910.1038/nrd208916883303
    [Google Scholar]
  10. KleinC.A. Cancer progression and the invisible phase of metastatic colonization.Nat. Rev. Cancer2020201168169410.1038/s41568‑020‑00300‑633024261
    [Google Scholar]
  11. PeartO. Metastatic breast cancer.Radiol. Technol.2017885519M539M28500107
    [Google Scholar]
  12. LangleyR.R. FidlerI.J. The seed and soil hypothesis revisited—The role of tumor‐stroma interactions in metastasis to different organs.Int. J. Cancer2011128112527253510.1002/ijc.2603121365651
    [Google Scholar]
  13. MarusicK. A New War on Cancer: The Unlikely Heroes Revolutionizing Prevention.Island Press2023
    [Google Scholar]
  14. KennedyR.F.Jr Limited boxed set: The real anthony fauci: Bill gates, big pharma, and the global war on democracy and public health.Simon and Schuster2023
    [Google Scholar]
  15. SunY. PengZ-L. Programmed cell death and cancer.Postgrad. Med. J.200985100113414010.1136/pgmj.2008.07262919351640
    [Google Scholar]
  16. ZörnigM. HueberA-O. BaumW. EvanG. Apoptosis regulators and their role in tumorigenesis. Biochimica et Biophysica Acta (BBA)-.Rev. Can.200115512F1F37
    [Google Scholar]
  17. AntolinA. WorkmanP. MestresJ. Al-LazikaniB. Polypharmacology in precision oncology: current applications and future prospects.Curr. Pharm. Des.201722466935694510.2174/138161282266616092311582827669965
    [Google Scholar]
  18. WethF.R. HoggarthG.B. WethA.F. PatersonE. WhiteM.P. TanS.T. PengL. GrayC. Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy.Br. J. Cancer202311338012383
    [Google Scholar]
  19. GuoT. MaS. Recent advances in the discovery of multitargeted tyrosine kinase inhibitors as anticancer agents.ChemMedChem202116460062010.1002/cmdc.20200065833179854
    [Google Scholar]
  20. ZhengP.P. LiJ. KrosJ.M. Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights.Med. Res. Rev.201838132537610.1002/med.2146328862319
    [Google Scholar]
  21. BibleK.C. KebebewE. BrierleyJ. BritoJ.P. CabanillasM.E. ClarkT.J.Jr Di CristofanoA. FooteR. GiordanoT. KasperbauerJ. NewboldK. NikiforovY.E. RandolphG. RosenthalM.S. SawkaA.M. ShahM. ShahaA. SmallridgeR. Wong-ClarkC.K. 2021 American thyroid association guidelines for management of patients with anaplastic thyroid cancer: American thyroid association anaplastic thyroid cancer guidelines task force.Thyroid202131333738610.1089/thy.2020.094433728999
    [Google Scholar]
  22. Pérez-HerreroE. Fernández-MedardeA. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy.Eur. J. Pharm. Biopharm.201593527910.1016/j.ejpb.2015.03.01825813885
    [Google Scholar]
  23. KeefeD.M.K. BatemanE.H. Tumor control versus adverse events with targeted anticancer therapies.Nat. Rev. Clin. Oncol.2012929810910.1038/nrclinonc.2011.19222182972
    [Google Scholar]
  24. SchmidingerM. Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors.Eur. J. Cancer, Suppl.201311217219110.1016/j.ejcsup.2013.07.01626217127
    [Google Scholar]
  25. PandeyA.K. SinghiE.K. ArroyoJ.P. IkizlerT.A. GouldE.R. BrownJ. BeckmanJ.A. HarrisonD.G. MoslehiJ. Mechanisms of VEGF (vascular endothelial growth factor) inhibitor–associated hypertension and vascular disease.Hypertension2018712e1e810.1161/HYPERTENSIONAHA.117.1027129279311
    [Google Scholar]
  26. TaberneroJ. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents.Mol. Cancer Res.20075320322010.1158/1541‑7786.MCR‑06‑040417374728
    [Google Scholar]
  27. LongoR. GaspariniG. Challenges for patient selection with VEGF inhibitors.Cancer Chemother. Pharmacol.200760215117010.1007/s00280‑006‑0403‑617370072
    [Google Scholar]
  28. DudaD.G. BatchelorT.T. WillettC.G. JainR.K. VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects.Trends Mol. Med.200713622323010.1016/j.molmed.2007.04.00117462954
    [Google Scholar]
  29. JinH. WangL. BernardsR. Rational combinations of targeted cancer therapies: background, advances and challenges.Nat. Rev. Drug Discov.202322321323410.1038/s41573‑022‑00615‑z36509911
    [Google Scholar]
  30. MoreiraS.I. FernandesA.P. RamosJ.M. Vascular endothelial growth factor (VEGF) inhibition-A critical review.Anti-cancer Agent. Med. Chem.200772223245
    [Google Scholar]
  31. RoskoskiR.Jr Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas.Pharmacol. Res.201712011613210.1016/j.phrs.2017.03.01028330784
    [Google Scholar]
  32. BaudinoT. T. Targeted cancer therapy: the next generation of cancer treatment.Curr. Drug Discov. Technol.201512132010.2174/157016381266615060214431026033233
    [Google Scholar]
  33. AdvaniA.S. CarrawayH.E. KarpJ.E. HorakI.D. Acute lymphoblastic leukemia and lymphoma in adults.The Lymphoid NeoplasmsCRC Press2010
    [Google Scholar]
  34. NikolicI. LeivaM. SabioG. The role of stress kinases in metabolic disease.Nat. Rev. Endocrinol.2020161269771610.1038/s41574‑020‑00418‑533067545
    [Google Scholar]
  35. LaganàA. VitaleS. NigroA. SofoV. SalmeriF. RossettiP. RapisardaA. La VigneraS. CondorelliR. RizzoG. BuscemaM. Pleiotropic actions of peroxisome proliferator-activated receptors (PPARs) in dysregulated metabolic homeostasis, inflammation and cancer: current evidence and future perspectives.Int. J. Mol. Sci.201617799910.3390/ijms1707099927347932
    [Google Scholar]
  36. FerraraN. Role of vascular endothelial growth factor in the regulation of angiogenesis.Kidney Int.199956379481410.1046/j.1523‑1755.1999.00610.x10469350
    [Google Scholar]
  37. GhalehbandiS. YuzugulenJ. PranjolM.Z.I. PourgholamiM.H. The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF.Eur. J. Pharmacol.202394917558610.1016/j.ejphar.2023.17558636906141
    [Google Scholar]
  38. CarmelietP. VEGF as a key mediator of angiogenesis in cancer.Oncology200569Suppl. 341010.1159/00008847816301830
    [Google Scholar]
  39. GuptaM.K. QinR-Y. Mechanism and its regulation of tumor-induced angiogenesis.World J. Gastroenterol.2003961144115510.3748/wjg.v9.i6.114412800214
    [Google Scholar]
  40. GudeR.P. PatilP. KamranM.Z. GoelP.N. Development of novel anti-cancer strategies based on angiogenesis inhibition.Anti-Angiogenesis Drug Discovery and Development.Elsevier201414719010.1016/B978‑0‑12‑803963‑2.50005‑3
    [Google Scholar]
  41. KitimuS.R. KiriraP. AbdilleA.A. SokeiJ. Ochwang’iD. MwitariP. MakanyaA. MainaN. Anti-angiogenic and anti-metastatic effects of biogenic silver nanoparticles synthesized using Azadirachta indica.Adv. Biosci. Biotechnol.202213418820610.4236/abb.2022.134010
    [Google Scholar]
  42. FarghalyT.A. Al-HasaniW.A. AbdulwahabH.G. An updated patent review of VEGFR-2 inhibitors (2017-present).Expert Opin. Ther. Pat.20213111989100710.1080/13543776.2021.193587234043477
    [Google Scholar]
  43. GardnerV. MaduC.O. LuY. Anti-VEGF therapy in cancer: A double-edged sword.Physiologic and pathologic angiogenesis-signaling mechanisms and targeted therapyIntechopen2017
    [Google Scholar]
  44. NitulescuG.M. StancovG. SeremetO.C. NitulescuG. MihaiD.P. Duta-BratuC.G. BarbuceanuS.F. OlaruO.T. The importance of the pyrazole scaffold in the design of protein kinases inhibitors as targeted anticancer therapies.Molecules20232814535910.3390/molecules2814535937513232
    [Google Scholar]
  45. AbdullazizM.A. Abdel-MohsenH.T. El KerdawyA.M. RagabF.A.F. AliM.M. Abu-bakrS.M. GirgisA.S. El DiwaniH.I. Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors.Eur. J. Med. Chem.201713631532910.1016/j.ejmech.2017.04.06828505536
    [Google Scholar]
  46. IsmailM.M.F. ShawerT.Z. IbrahimR.S. AbusaifM.S. KamalM.M. AllamR.M. AmmarY.A. Novel quinoxaline-3-propanamides as VGFR-2 inhibitors and apoptosis inducers.RSC Advances20231345319083192410.1039/D3RA05066A37915441
    [Google Scholar]
  47. FischerA. SmieškoM. Allosteric binding sites on nuclear receptors: Focus on drug efficacy and selectivity.Int. J. Mol. Sci.202021253410.3390/ijms2102053431947677
    [Google Scholar]
  48. De AmiciM. DallanoceC. HolzgrabeU. TränkleC. MohrK. Allosteric ligands for G protein-coupled receptors: A novel strategy with attractive therapeutic opportunities.Med. Res. Rev.201030346354910.1002/med.2016619557759
    [Google Scholar]
  49. AkhtarN. KhanR.A. Liposomal systems as viable drug delivery technology for skin cancer sites with an outlook on lipid-based delivery vehicles and diagnostic imaging inputs for skin conditions’.Prog. Lipid Res.20166419223010.1016/j.plipres.2016.08.00527697511
    [Google Scholar]
  50. DristantU. MukherjeeK. SahaS. MaityD. An overview of polymeric nanoparticles-based drug delivery system in cancer treatment.Technol. Cancer Res. Treat.2023221533033823115208310.1177/1533033823115208336718541
    [Google Scholar]
  51. TeixeiraM.C. CarboneC. SoutoE.B. Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery.Prog. Lipid Res.20176811110.1016/j.plipres.2017.07.00128778472
    [Google Scholar]
  52. BuseJ. El-AneedA. Properties, engineering and applications of lipid-based nanoparticle drug-delivery systems: current research and advances.Nanomedicine (Lond.)2010581237126010.2217/nnm.10.10721039200
    [Google Scholar]
  53. KalomirakiM. ThermosK. ChaniotakisN.A. Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications.Int. J. Nanomedicine20151111226730187
    [Google Scholar]
  54. NorouziM. NazariB. MillerD.W. Injectable hydrogel-based drug delivery systems for local cancer therapy.Drug Discov. Today201621111835184910.1016/j.drudis.2016.07.00627423369
    [Google Scholar]
  55. Abdel-MohsenH.T. IbrahimM.A. NageebA.M. El KerdawyA.M. Receptor-based pharmacophore modeling, molecular docking, synthesis and biological evaluation of novel VEGFR-2, FGFR-1, and BRAF multi-kinase inhibitors.BMC Chem.20241814210.1186/s13065‑024‑01135‑038395926
    [Google Scholar]
  56. FouadM.A. OsmanA.A. AbdelhamidN.M. RashadM.W. NabawyA.Y. El KerdawyA.M. Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual screening, and molecular docking studies.BMC Chem.20241812910.1186/s13065‑024‑01130‑538347617
    [Google Scholar]
  57. YadavM. KhandelwalR. MudgalU. SrinithaS. KhandekarN. NayarisseriA. VureeS. SinghS.K. Identification of potent VEGF inhibitors for the clinical treatment of glioblastoma, a virtual screening approach.Asian Pac. J. Cancer Prev.20192092681269210.31557/APJCP.2019.20.9.268131554364
    [Google Scholar]
  58. SchmidtF. MatterH. HesslerG. CzichA. Predictive in silico off-target profiling in drug discovery.Future Med. Chem.20146329531710.4155/fmc.13.20224575966
    [Google Scholar]
  59. ElkamhawyA. AliE.M.H. LeeK. New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011–2021) focussing on structure–activity relationship (SAR) and docking insights.J. Enzyme Inhib. Med. Chem.20213611572160010.1080/14756366.2021.193714334233563
    [Google Scholar]
  60. Van VleetT.R. LiguoriM.J. LynchJ.J. RaoM. WarderS. Screening strategies and methods for better off-target liability prediction and identification of small-molecule pharmaceuticals.Adv. Life Sci.2019241124
    [Google Scholar]
  61. FinnR.S. Current and future treatment strategies for patients with advanced hepatocellular carcinoma: role of mTOR inhibition.Liver Cancer201213-424725610.1159/00034383924159589
    [Google Scholar]
  62. LyonA.R. DentS. StanwayS. EarlH. Brezden-MasleyC. Cohen-SolalA. TocchettiC.G. MoslehiJ.J. GroarkeJ.D. Bergler-KleinJ. KhooV. TanL.L. AnkerM.S. von HaehlingS. MaackC. PudilR. BaracA. ThavendiranathanP. KyB. NeilanT.G. BelenkovY. RosenS.D. IakobishviliZ. SverdlovA.L. HajjarL.A. MacedoA.V.S. ManistyC. CiardielloF. FarmakisD. de BoerR.A. SkouriH. SuterT.M. CardinaleD. WittelesR.M. FradleyM.G. HerrmannJ. CornellR.F. WechelakerA. MauroM.J. MilojkovicD. de LavalladeH. RuschitzkaF. CoatsA.J.S. SeferovicP.M. ChioncelO. ThumT. BauersachsJ. AndresM.S. WrightD.J. López-FernándezT. PlummerC. LenihanD. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: A position statement and new risk assessment tools from the cardio‐oncology study group of the heart failure association of the European society of cardiology in collaboration with the international cardio‐oncology society.Eur. J. Heart Fail.202022111945196010.1002/ejhf.192032463967
    [Google Scholar]
  63. FerraraNapoleone. VEGF as a therapeutic target in cancer.Oncol.69, Suppl. 3, 2005, 11-16.
    [Google Scholar]
  64. MohamedT.K. BatranR.Z. ElseginyS.A. AliM.M. MahmoudA.E. Synthesis, anticancer effect and molecular modeling of new thiazolylpyrazolyl coumarin derivatives targeting VEGFR-2 kinase and inducing cell cycle arrest and apoptosis.Bioorg. Chem.20198525327310.1016/j.bioorg.2018.12.04030641320
    [Google Scholar]
  65. PalK. MadamsettyV.S. DuttaS.K. MukhopadhyayD. Co-delivery of everolimus and vinorelbine via a tumor-targeted liposomal formulation inhibits tumor growth and metastasis in RCC.Int. J. Nanomedicine2019145109512310.2147/IJN.S20422131371950
    [Google Scholar]
  66. AlbigesL. GizziM. CartonE. EscudierB. Axitinib in metastatic renal cell carcinoma.Expert Rev. Anticancer Ther.201515549950710.1586/14737140.2015.103340825907705
    [Google Scholar]
  67. BracardaS. CastellanoD. ProcopioG. SepúlvedaJ.M. SisaniM. VerzoniE. SchmidingerM. Axitinib safety in metastatic renal cell carcinoma: suggestions for daily clinical practice based on case studies.Expert Opin. Drug Saf.201413449751010.1517/14740338.2014.88841324641566
    [Google Scholar]
  68. EscudierB. WordenF. KudoM. Sorafenib: key lessons from over 10 years of experience.Expert Rev. Anticancer Ther.201919217718910.1080/14737140.2019.155905830575405
    [Google Scholar]
  69. LiQ. ChengX. ZhouC. TangY. LiF. ZhangB. HuangT. WangJ. TuS. Fruquintinib enhances the antitumor immune responses of anti-programmed death receptor-1 in colorectal cancer.Front. Oncol.20221284197710.3389/fonc.2022.84197735371995
    [Google Scholar]
  70. PatellK. MearsV. L. StorandtM.H. MahipalA. Metabolism, toxicity and management of fruquintinib: a novel drug for metastatic colorectal cancer.Expert Opin. Drug Metabol. Toxicol.2024204236410.1080/17425255.2024.2332364
    [Google Scholar]
  71. Mulet-MargalefN. Garcia del MuroX. Sunitinib in the treatment of gastrointestinal stromal tumor: patient selection and perspectives.OncoTargets Ther.201697573758210.2147/OTT.S10138528008275
    [Google Scholar]
  72. BroseM.S. NuttingC.M. JarzabB. EliseiR. SienaS. BastholtL. de la FouchardiereC. PaciniF. PaschkeR. ShongY.K. ShermanS.I. SmitJ.W.A. ChungJ. KappelerC. PeñaC. MolnárI. SchlumbergerM.J. DECISION investigators Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.Lancet2014384994031932810.1016/S0140‑6736(14)60421‑924768112
    [Google Scholar]
  73. JászaiJ. SchmidtM. Trends and challenges in tumor anti-angiogenic therapies.Cells201989110210.3390/cells809110231540455
    [Google Scholar]
  74. RanieriG. MammìM. Donato Di PaolaE. RussoE. GallelliL. CitraroR. GadaletaC.D. MarechI. AmmendolaM. De SarroG. Pazopanib a tyrosine kinase inhibitor with strong anti-angiogenetic activity: A new treatment for metastatic soft tissue sarcoma.Crit. Rev. Oncol. Hematol.201489232232910.1016/j.critrevonc.2013.08.01224041629
    [Google Scholar]
  75. ShamroeC.L. ComeauJ.M. Ponatinib.Ann. Pharmacother.201347111540154610.1177/106002801350114424265264
    [Google Scholar]
  76. PrasadV. MailankodyS. The accelerated approval of oncologic drugs: lessons from ponatinib.JAMA2014311435335410.1001/jama.2013.28453124449310
    [Google Scholar]
  77. SiaD. AlsinetC. NewellP. VillanuevaA. VEGF signaling in cancer treatment.Curr. Pharm. Des.201420172834284210.2174/1381612811319999059023944367
    [Google Scholar]
  78. ShinkarukS. BayleM. LaïnG. DélérisG. Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy.Curr. Med. Chem. Anticancer Agents2003329511710.2174/156801103335345212678905
    [Google Scholar]
  79. SimonsM. GordonE. Claesson-WelshL. Mechanisms and regulation of endothelial VEGF receptor signalling.Nat. Rev. Mol. Cell Biol.2016171061162510.1038/nrm.2016.8727461391
    [Google Scholar]
  80. FuhG. WuP. LiangW.C. UltschM. LeeC.V. MoffatB. WiesmannC. Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab.J. Biol. Chem.2006281106625663110.1074/jbc.M50778320016373345
    [Google Scholar]
  81. WoodJeanette M. Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy.Medicina-Buenos Aires60, 2000, 41-47.
    [Google Scholar]
  82. AminiA. Masoumi MoghaddamS. MorrisD.L. PourgholamiM.H. The critical role of vascular endothelial growth factor in tumor angiogenesis.Curr. Cancer Drug Targets2012121234310.2174/15680091279888895622111836
    [Google Scholar]
  83. SaharinenP. EklundL. PulkkiK. BonoP. AlitaloK. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis.Trends Mol. Med.201117734736210.1016/j.molmed.2011.01.01521481637
    [Google Scholar]
  84. Leite de OliveiraR. HammA. MazzoneM. Growing tumor vessels: More than one way to skin a cat – Implications for angiogenesis targeted cancer therapies.Mol. Aspects Med.2011322718710.1016/j.mam.2011.04.00121540050
    [Google Scholar]
  85. KiselyovA. BalakinK.V. TkachenkoS.E. VEGF/VEGFR signalling as a target for inhibiting angiogenesis.Expert Opin. Investig. Drugs20071618310710.1517/13543784.16.1.8317155856
    [Google Scholar]
  86. ByrneA.M. Bouchier-HayesD.J. HarmeyJ.H. Angiogenic and cell survival functions of Vascular Endothelial Growth Factor (VEGF).J. Cell. Mol. Med.20059477779410.1111/j.1582‑4934.2005.tb00379.x16364190
    [Google Scholar]
  87. FakhriS. AbbaszadehF. JorjaniM. PourgholamiM.H. The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: a review study.Nutr. Cancer202173111510.1080/01635581.2019.167345131648565
    [Google Scholar]
  88. MalekanM. EbrahimzadehM.A. Vascular endothelial growth factor receptors [VEGFR] as target in breast cancer treatment: current status in preclinical and clinical studies and future directions.Curr. Top. Med. Chem.2022221189192010.2174/156802662266622030816171035260067
    [Google Scholar]
  89. MarzoukA.A. Abdel-AzizS.A. AbdelrahmanK.S. WanasA.S. GoudaA.M. YoussifB.G.M. Abdel-AzizM. Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation.Bioorg. Chem.202010210409010.1016/j.bioorg.2020.10409032683176
    [Google Scholar]
  90. Al-MuntaserS.M. Al-KarmalawyA.A. El-NaggarA.M. AliA.K. Abd El-SattarN.E.A. AbbassE.M. Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, and in silico studies.RSC Advances20231318121841220310.1039/D3RA00416C37082377
    [Google Scholar]
  91. RuziZ. BozorovK. NieL. ZhaoJ. AisaH.A. Novel pyrazolo[3,4-d]pyrimidines as potential anticancer agents: Synthesis, VEGFR-2 inhibition, and mechanisms of action.Biomed. Pharmacother.202215611394810.1016/j.biopha.2022.11394836411633
    [Google Scholar]
  92. MghwaryA.E.S. GedawyE.M. KamalA.M. Abuel-MaatyS.M. Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile.J. Enzyme Inhib. Med. Chem.201934183885210.1080/14756366.2019.159316030919701
    [Google Scholar]
  93. Abd El-MageedM.M.A. EissaA.A.M. FaragA.E.S. OsmanE.E.A. Design and synthesis of novel furan, furo[2,3-d]pyrimidine and furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as potential VEGFR-2 inhibitors.Bioorg. Chem.202111610533610.1016/j.bioorg.2021.10533634530235
    [Google Scholar]
  94. El-MetwallyS.A. ElkadyH. HagrasM. HuseinD.Z. IbrahimI.M. TaghourM.S. El-MahdyH.A. IsmailA. AlsfoukB.A. ElkaeedE.B. MetwalyA.M. EissaI.H. Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3- d ]pyrimidines targeting VEGFR-2.RSC Advances20231333233652338510.1039/D3RA03128D37545598
    [Google Scholar]
  95. Abdel-MohsenH.T. GirgisA.S. MahmoudA.E.E. AliM.M. El DiwaniH.I. New 2,4‐disubstituted‐2‐thiopyrimidines as VEGFR‐2 inhibitors: Design, synthesis, and biological evaluation.Arch. Pharm. (Weinheim)201935211190008910.1002/ardp.20190008931463965
    [Google Scholar]
  96. CuartasV. Aragón-MurielA. LiscanoY. Polo-CerónD. Crespo-OrtizM.P. QuirogaJ. AboniaR. InsuastyB. Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis, DNA binding and molecular docking.RSC Advances20211138233102332910.1039/D1RA03509F35479808
    [Google Scholar]
  97. FaroukA.K.B.A.W. Abdelrasheed AllamH. RashwanE. GeorgeR.F. AbbasS.E.S. Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors.Bioorg. Chem.202212810609910.1016/j.bioorg.2022.10609935994884
    [Google Scholar]
  98. AbdallahA.E. MabroukR.R. Al WardM.M.S. EissaS.I. ElkaeedE.B. MehanyA.B.M. Abo-SaifM.A. El-FekyO.A. AlesawyM.S. El-ZahabiM.A. Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors.J. Enzyme Inhib. Med. Chem.202237157359110.1080/14756366.2021.201791135012403
    [Google Scholar]
  99. WeiD. FanH. ZhengK. QinX. YangL. YangY. DuanY. ZhangQ. ZengC. HuL. Synthesis and anti-tumor activity of [1,4] dioxino[2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2.Bioorg. Chem.20198810291610.1016/j.bioorg.2019.04.01031026719
    [Google Scholar]
  100. WangR. LiuH. YouY.Y. WangX.Y. LvB.B. CaoL.Q. XueJ.Y. XuY.G. ShiL. Discovery of novel VEGFR-2 inhibitors embedding 6,7-dimethoxyquinazoline and diarylamide fragments.Bioorg. Med. Chem. Lett.20213612778810.1016/j.bmcl.2021.12778833460739
    [Google Scholar]
  101. EissaI.H. El-HelbyA.G.A. MahdyH.A. KhalifaM.M. ElnagarH.A. MehanyA.B.M. MetwalyA.M. ElhendawyM.A. RadwanM.M. ElSohlyM.A. El-AdlK. Discovery of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors: Design, synthesis, and anti-proliferative evaluation.Bioorg. Chem.202010510438010.1016/j.bioorg.2020.10438033128967
    [Google Scholar]
  102. ZhaoY. LiuF. HeG. LiK. ZhuC. YuW. ZhangC. XieM. LinJ. ZhangJ. JinY. Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking.Bioorg. Med. Chem. Lett.2019292312671110.1016/j.bmcl.2019.12671131668972
    [Google Scholar]
  103. WeiH. DuanY. GouW. CuiJ. NingH. LiD. QinY. LiuQ. LiY. Design, synthesis and biological evaluation of novel 4-anilinoquinazoline derivatives as hypoxia-selective EGFR and VEGFR-2 dual inhibitors.Eur. J. Med. Chem.201918111155210.1016/j.ejmech.2019.07.05531387063
    [Google Scholar]
  104. El-AdlK. SakrH.M. YousefR.G. MehanyA.B.M. MetwalyA.M. ElhendawyM.A. RadwanM.M. ElSohlyM.A. AbulkhairH.S. EissaI.H. Discovery of new quinoxaline-2(1H)-one-based anticancer agents targeting VEGFR-2 as inhibitors: Design, synthesis, and anti-proliferative evaluation.Bioorg. Chem.202111410510510.1016/j.bioorg.2021.10510534175720
    [Google Scholar]
  105. AhmedM.F. SantaliE.Y. Discovery of pyridine- sulfonamide hybrids as a new scaffold for the development of potential VEGFR-2 inhibitors and apoptosis inducers.Bioorg. Chem.202111110484210.1016/j.bioorg.2021.10484233798847
    [Google Scholar]
  106. SalehN.M. El-GabyM.S.A. El-AdlK. Abd El-SattarN.E.A. Design, green synthesis, molecular docking and anticancer evaluations of diazepam bearing sulfonamide moieties as VEGFR-2 inhibitors.Bioorg. Chem.202010410435010.1016/j.bioorg.2020.10435033142416
    [Google Scholar]
  107. Al-WarhiT. AbualnajaM. Abu AliO.A. AlyamaniN.M. ElsaidF.G. ShatiA.A. AlbogamiS. FayadE. Abu AlmaatyA.H. MohamedK.O. AlamoudiW.M. ZakiI. Design, synthesis and cytotoxicity screening of new thiazole derivatives as potential anticancer agents through VEGFR-2 inhibition.Symmetry (Basel)2022149181410.3390/sym14091814
    [Google Scholar]
  108. Al-SaneaM.M. HamdiA. MohamedA.A.B. El-ShafeyH.W. MoustafaM. ElgazarA.A. EldehnaW.M. Ur RahmanH. ParambiD.G.T. ElbargisyR.M. SelimS. BukhariS.N.A. Magdy HendawyO. TawfikS.S. New benzothiazole hybrids as potential VEGFR-2 inhibitors: design, synthesis, anticancer evaluation, and in silico study.J. Enzyme Inhib. Med. Chem.2023381216603610.1080/14756366.2023.216603636691927
    [Google Scholar]
  109. OthmanI.M.M. AlamshanyZ.M. TashkandiN.Y. Gad-ElkareemM.A.M. Abd El-KarimS.S. NossierE.S. Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors.RSC Advances202112156157710.1039/D1RA08055E35424523
    [Google Scholar]
  110. SalehN.M. El-GazzarM.G. AlyH.M. OthmanR.A. Novel anticancer fused pyrazole derivatives as EGFR and VEGFR-2 dual TK inhibitors.Front Chem.2020791710.3389/fchem.2019.0091732039146
    [Google Scholar]
  111. Abd El-LateefH.M. ElbastawesyM.A.I. Abdelghani IbrahimT.M. KhalafM.M. GoudaM. WahbaM.G.F. ZakiI. MorcossM.M. Design, synthesis, docking study, and antiproliferative evaluation of novel schiff base–benzimidazole hybrids with VEGFR-2 inhibitory activity.Molecules202328248110.3390/molecules2802048136677536
    [Google Scholar]
  112. YuanX. YangQ. LiuT. LiK. LiuY. ZhuC. ZhangZ. LiL. ZhangC. XieM. LinJ. ZhangJ. JinY. Design, synthesis and in vitro evaluation of 6-amide-2-aryl benzoxazole/benzimidazole derivatives against tumor cells by inhibiting VEGFR-2 kinase.Eur. J. Med. Chem.201917914716510.1016/j.ejmech.2019.06.05431252306
    [Google Scholar]
  113. ZeidanM.A. MostafaA.S. GomaaR.M. Abou-zeidL.A. El-MeseryM. El-SayedM.A.A. SelimK.B. Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors.Eur. J. Med. Chem.201916831532910.1016/j.ejmech.2019.02.05030826508
    [Google Scholar]
  114. El-AdlK. El-HelbyA.A. SakrH. EissaI.H. El-HddadS.S.A. M I A ShomanF. Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme.Bioorg. Chem.202010210405910.1016/j.bioorg.2020.10405932653608
    [Google Scholar]
  115. ElkaeedE.B. YousefR.G. ElkadyH. GobaaraI.M.M. AlsfoukB.A. HuseinD.Z. IbrahimI.M. MetwalyA.M. EissaI.H. Design, synthesis, docking, DFT, MD simulation studies of a new nicotinamide-based derivative: In vitro anticancer and VEGFR-2 inhibitory effects.Molecules20222714460610.3390/molecules2714460635889478
    [Google Scholar]
  116. LiuX. LiY. ZhangQ. PanQ. ZhengP. DaiX. BaiZ. ZhuW. Design, synthesis, and biological evaluation of [1, 2, 4] triazolo[4, 3-a] pyrazine derivatives as novel dual c-Met/VEGFR-2 inhibitors.Front Chem.20221081553410.3389/fchem.2022.81553435464202
    [Google Scholar]
  117. AbdelsalamE.A. Abd El-HafeezA.A. EldehnaW.M. El HassabM.A. MarzoukH.M.M. ElaasserM.M. Abou TalebN.A. AminK.M. Abdel-AzizH.A. GhoshP. HammadS.F. Discovery of novel thiazolyl-pyrazolines as dual EGFR and VEGFR-2 inhibitors endowed with in vitro antitumor activity towards non-small lung cancer.J. Enzyme Inhib. Med. Chem.20223712265228210.1080/14756366.2022.210484136000167
    [Google Scholar]
  118. AbdelHaleemA. MansourA.O. AbdelKaderM. ArafaR.K. Selective VEGFR-2 inhibitors: Synthesis of pyridine derivatives, cytotoxicity and apoptosis induction profiling.Bioorg. Chem.202010310422210.1016/j.bioorg.2020.10422232889383
    [Google Scholar]
  119. Al-WarhiT. SallamA.A. HemedaL. El HassabM. AljaeedN. AlotaibiO. DoghishA. NoshyM. EldehnaW. IbrahimM. Identification of novel cyanopyridones and pyrido[2, 3-D] pyrimidines as anticancer agents with dual VEGFR-2/HER-2 inhibitory action: synthesis, biological evaluation and molecular docking studies.Pharmaceuticals (Basel)20221510126210.3390/ph1510126236297374
    [Google Scholar]
  120. RaslanR.R. AmmarY.A. FouadS.A. HesseinS.A. ShmiessN.A.M. RagabA. Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′ H -spiro-pyridine derivatives as a new class of EGFR Wt and VEGFR-2 inhibitors with apoptotic inducers.RSC Advances20231315104401045810.1039/D3RA00887H37020892
    [Google Scholar]
  121. WardaE.T. ShehataI.A. El-AshmawyM.B. El-GoharyN.S. New series of isoxazole derivatives targeting EGFR-TK: Synthesis, molecular modeling and antitumor evaluation.Bioorg. Med. Chem.2020282111567410.1016/j.bmc.2020.11567433065442
    [Google Scholar]
  122. ShenF.Q. ShiL. WangZ.F. WangC.R. ChenJ.J. LiuY. QiuH.Y. ZhuH.L. Design, synthesis, biological evaluation of benzoyl amide derivatives containing nitrogen heterocyclic ring as potential VEGFR-2 inhibitors.Bioorg. Med. Chem.201927173813382410.1016/j.bmc.2019.07.00731327679
    [Google Scholar]
  123. Merdeİ.B. ÖnelG.T. AkkoçS. KaraköyZ. TürkmenoğluB. Focusing on new piperazinyl‐methyl‐3 (2H) pyridazinone based derivatives: Design, synthesis, anticancer activity and computational studies.ChemistrySelect2023825e20230091010.1002/slct.202300910
    [Google Scholar]
  124. EzelarabH.A. AliT.F. AbbasS.H. SayedA.M. BeshrE.A. HassanH.A. New antiproliferative 3-substituted oxindoles inhibiting EGFR/VEGFR-2 and tubulin polymerization.Mol. Divers.202311836790582
    [Google Scholar]
  125. AbdelgawadM.A. HayallahA.M. BukhariS.N.A. MusaA. ElmowafyM. Abdel-RahmanH.M. Abd El-GaberM.K. Design, synthesis, molecular modeling, and anticancer evaluation of new VEGFR-2 inhibitors based on the indolin-2-One scaffold.Pharmaceuticals (Basel)20221511141610.3390/ph1511141636422546
    [Google Scholar]
  126. KassabA.E. GedawyE.M. HamedM.I.A. DoghishA.S. HassanR.A. Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers.J. Enzyme Inhib. Med. Chem.202136192293910.1080/14756366.2021.190108933896327
    [Google Scholar]
  127. YaseenY. KubbaA. ShihabW. TahtamouniL. Synthesis, docking study, and structureactivity relationship of novel niflumic acid derivatives acting as anticancer agents by inhibiting VEGFR or EGFR tyrosine kinase activities.Pharmacia2022693595614
    [Google Scholar]
  128. El-SayedW.A. AlminderejF.M. MounierM.M. NossierE.S. SalehS.M. F KassemA. NewA. 1, 2, 3-Triazole-Coumarin-Glycoside Hybrids and Their 1, 2, 4-triazolyl thioglycoside analogs targeting mitochondria apoptotic pathway: Synthesis, anticancer activity and docking simulation.Molecules20222717568810.3390/molecules2717568836080455
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206356712241202112641
Loading
/content/journals/acamc/10.2174/0118715206356712241202112641
Loading

Data & Media loading...

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