{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:47:00Z","timestamp":1791463620190,"version":"4.3.4"},"reference-count":36,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: A promising anticancer strategy is the simultaneous inhibition of the receptor tyrosine kinases VEGFR-2 and c-Met, which are essential for tumor angiogenesis, growth, and metastasis. In this study, a novel series of piperidinyl-based benzoxazole derivatives was designed and synthesized as potential dual VEGFR-2\/c-Met inhibitors. Methods: The kinase inhibitory potential of the derivatives was evaluated in comparison to reference inhibitors, Sorafenib (VEGFR-2 inhibitor) and Staurosporine (c-Met inhibitor). Cytotoxicity was assessed across breast, prostate (PC-3), and lung (A549) cancer cell lines. Mechanistic studies included cell-cycle analysis, apoptosis assays, gene expression profiling of apoptosis-related markers, and molecular docking within the ATP-binding pockets of both kinases. Results: Compounds 5a, 5g, 5h, 11a, and 11b showed strong inhibition of both kinases (IC50 = 0.145\u20130.970 \u03bcM for VEGFR-2 and 0.181\u20131.885 \u03bcM for c-Met). Selective cytotoxicity was observed against breast cancer cells, with compound 11b (p-fluorophenyl derivative) exhibiting high selectivity toward MCF-7 over normal breast cells (MCF-10A) and potency comparable to or exceeding Sorafenib. Mechanistically, 11b induced G2\/M cell-cycle arrest and apoptosis (total apoptosis = 48.34%), accompanied by upregulation of p53, BAX, and caspase-9 and downregulation of Bcl-2. Molecular docking confirmed stable binding within the ATP-binding sites of both kinases. Conclusions: Compound 11b was established as a novel, selective, dual VEGFR-2\/c-Met inhibitor with strong potential for targeted breast cancer therapy.<\/jats:p>","DOI":"10.3390\/ph18121875","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T15:50:02Z","timestamp":1765295402000},"page":"1875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Discovery of Novel Piperidinyl-Based Benzoxazole Derivatives as Anticancer Agents Targeting VEGFR-2 and c-Met Kinases"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6996-4017","authenticated-orcid":false,"given":"Wagdy M.","family":"Eldehna","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Shaikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab M.","family":"Elsayed","sequence":"additional","affiliation":[{"name":"Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Shaikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-2369","authenticated-orcid":false,"given":"Mohamed R.","family":"Elnagar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11823, Egypt"},{"name":"Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf 54001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H.","family":"El-Said","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa 11152, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taghreed A.","family":"Majrashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, King Khalid University, Asir 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3399-3435","authenticated-orcid":false,"given":"Ahmed T.","family":"Negmeldin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5153-7399","authenticated-orcid":false,"given":"Abdulrahman M.","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2690-0192","authenticated-orcid":false,"given":"Ranza","family":"Elrayess","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt"},{"name":"Pharmaceutical Organic Chemistry Department, College of Pharmacy, Al-Ayen Iraqi University (AUIQ), An Nasiriyah 64001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4378-1228","authenticated-orcid":false,"given":"Khaled A.","family":"Elnahriry","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9716-8368","authenticated-orcid":false,"given":"Zhi-Long","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science and Technology, Donghua University, Shanghai 201620, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1597-5324","authenticated-orcid":false,"given":"Mohamed","family":"Elagawany","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6455-5716","authenticated-orcid":false,"given":"Haytham O.","family":"Tawfik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s10555-024-10172-z","article-title":"Cancer cell plasticity: From cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance","volume":"43","author":"Bhat","year":"2024","journal-title":"Cancer Metastasis Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s12964-025-02173-4","article-title":"Unraveling the role of hypoxia-inducible factors in cutaneous melanoma: From mechanisms to therapeutic opportunities","volume":"23","author":"Bellazzo","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_3","first-page":"50","article-title":"Tumor angiogenesis and VEGFR-2: Mechanism, pathways and current biological therapeutic interventions","volume":"22","author":"Shah","year":"2021","journal-title":"Curr. Drug Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s12079-016-0352-8","article-title":"VEGF-A\/VEGFR2 signaling network in endothelial cells relevant to angiogenesis","volume":"10","author":"Abhinand","year":"2016","journal-title":"J. Cell Commun. Signal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"33384","DOI":"10.1039\/D4RA05244G","article-title":"Recent updates on potential of VEGFR-2 small-molecule inhibitors as anticancer agents","volume":"14","author":"Chaudhari","year":"2024","journal-title":"RSC Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.drup.2018.01.002","article-title":"Redundant angiogenic signaling and tumor drug resistance","volume":"36","author":"Gacche","year":"2018","journal-title":"Drug Resist. Updates"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12964-025-02033-1","article-title":"Targeting HGF\/c-MET signaling to regulate the tumor microenvironment: Implications for counteracting tumor immune evasion","volume":"23","author":"Xia","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s43094-024-00688-0","article-title":"Exploring the potential of small molecules of dual c-Met and VEGFR inhibitors for advances and future drug discovery in cancer therapy","volume":"10","author":"Dhawale","year":"2024","journal-title":"Future J. Pharm. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s40291-021-00568-w","article-title":"MET-targeted therapies and clinical outcomes: A systematic literature review","volume":"26","author":"Dong","year":"2022","journal-title":"Mol. Diagn. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.ejmech.2015.12.016","article-title":"Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs","volume":"108","author":"Zhang","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4173","DOI":"10.1158\/1078-0432.CCR-22-0873","article-title":"FDA approval summary: Cabozantinib for differentiated thyroid cancer","volume":"28","author":"Duke","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5420","DOI":"10.1016\/j.ejmech.2010.09.002","article-title":"Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors","volume":"45","author":"Lee","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/hep.29496","article-title":"Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma","volume":"67","author":"Bouattour","year":"2018","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1021\/jm9801004","article-title":"Benzoxazole Derivatives as Novel 5-HT3 Receptor Partial Agonists in the Gut","volume":"41","author":"Sato","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116527","DOI":"10.1016\/j.ejmech.2024.116527","article-title":"A new framework for novel analogues of pazopanib as potent and selective human carbonic anhydrase inhibitors: Design, repurposing rational, synthesis, crystallographic, in vivo and in vitro biological assessments","volume":"274","author":"Hefny","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1021\/acs.jmedchem.3c02279","article-title":"Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma","volume":"67","author":"Tawfik","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Garcia-Oliveira, P., Otero, P., Pereira, A.G., Chamorro, F., Carpena, M., Echave, J., Fraga-Corral, M., Simal-Gandara, J., and Prieto, M.A. (2021). Status and challenges of plant-anticancer compounds in cancer treatment. Pharmaceuticals, 14.","DOI":"10.3390\/ph14020157"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"348","DOI":"10.20892\/j.issn.2095-3941.2017.0033","article-title":"Cell cycle regulation and anticancer drug discovery","volume":"14","author":"Bai","year":"2017","journal-title":"Cancer Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, Z. (2021). Regulation of cell cycle progression by growth factor-induced cell signaling. Cells, 10.","DOI":"10.3390\/cells10123327"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1021\/cr900026u","article-title":"DNA structure and integrity checkpoints during the cell cycle and their role in drug targeting and sensitivity of tumor cells to anticancer treatment","volume":"109","author":"Skladanowski","year":"2009","journal-title":"Chem. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/j.1365-2796.2010.02282.x","article-title":"Cell cycle and cell death in disease: Past, present and future","volume":"268","author":"Zhivotovsky","year":"2010","journal-title":"J. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"205","DOI":"10.15171\/apb.2019.024","article-title":"Understanding apoptosis and apoptotic pathways targeted cancer therapeutics","volume":"9","author":"Jan","year":"2019","journal-title":"Adv. Pharm. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1634\/theoncologist.12-12-1395","article-title":"Proautophagic drugs: A novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas","volume":"12","author":"Lefranc","year":"2007","journal-title":"Oncologist"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1089\/clo.2009.0028","article-title":"Serum-starved apoptotic fibroblasts reduce blastocyst production but enable development to term after SCNT in cattle","volume":"11","author":"Miranda","year":"2009","journal-title":"Cloning Stem Cells"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1021\/acs.jmedchem.3c01708","article-title":"Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments","volume":"67","author":"Mousa","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5032","DOI":"10.1016\/j.bmc.2010.05.080","article-title":"Synthesis of a series of caffeic acid phenethyl amide (CAPA) fluorinated derivatives: Comparison of cytoprotective effects to caffeic acid phenethyl ester (CAPE)","volume":"18","author":"Yang","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1039\/D4MD00778F","article-title":"Donepezil-based rational design of N-substituted quinazolinthioacetamide candidates as potential acetylcholine esterase inhibitors for the treatment of Alzheimer\u2019s disease: In vitro and in vivo studies","volume":"16","author":"Mohamed","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7406","DOI":"10.1021\/acs.jmedchem.4c00239","article-title":"Discovery and mechanistic studies of dual-target hits for carbonic anhydrase IX and VEGFR-2 as potential agents for solid tumors: X-ray, in vitro, in vivo, and in silico investigations of coumarin-based thiazoles","volume":"67","author":"Hefny","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_29","first-page":"44","article-title":"The Synergy\u2122 HT: A unique multi-detection microplate reader for HTS and drug discovery","volume":"8","author":"Held","year":"2003","journal-title":"J. Assoc. Lab. Autom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"139074","DOI":"10.1016\/j.molstruc.2024.139074","article-title":"Design, synthesis and pharmacological evaluation of novel thiazole derivatives as c-Met kinase inhibitors and anticancer agents","volume":"1317","author":"Gediya","year":"2024","journal-title":"J. Mol. Struct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1038\/s41598-018-37796-w","article-title":"Cytotoxicity of eupatorin in MCF-7 and MDA-MB-231 human breast cancer cells via cell cycle arrest, anti-angiogenesis and induction of apoptosis","volume":"9","author":"Razak","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s12282-018-0912-2","article-title":"Griffipavixanthone induces apoptosis of human breast cancer MCF-7 cells in vitro","volume":"26","author":"Ma","year":"2019","journal-title":"Breast Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/j.bmcl.2015.02.002","article-title":"Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors","volume":"25","author":"Dorsch","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"18281","DOI":"10.1073\/pnas.1207759109","article-title":"Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors","volume":"109","author":"McTigue","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1875\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T05:22:05Z","timestamp":1765430525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1875"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,9]]},"references-count":36,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ph18121875"],"URL":"https:\/\/doi.org\/10.3390\/ph18121875","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,9]]}}}