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Among the designed series, Compounds\n                    <jats:bold>2h<\/jats:bold>\n                    and\n                    <jats:bold>2l<\/jats:bold>\n                    were the most potent derivatives across both tumor models, exhibiting IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 23.3 and 30.9\u2009\u03bcM (HCT\u2010116), respectively, and 31.5 and 39.2\u2009\u03bcM (MCF\u20107), respectively, compared to sorafenib (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20098.8 and 11.6\u2009\u03bcM, respectively). Interestingly,\n                    <jats:bold>2h<\/jats:bold>\n                    and\n                    <jats:bold>2l<\/jats:bold>\n                    displayed a favorable safety profile toward the normal human cell line WI\u201038, with IC\n                    <jats:sub>50<\/jats:sub>\n                    &gt;\u2009200\u2009\u03bcM comparable to sorafenib (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u2009192\u2009\u03bcM). In vitro enzymatic assays,\n                    <jats:bold>2h<\/jats:bold>\n                    and\n                    <jats:bold>2l<\/jats:bold>\n                    derivatives emerged as potent multi\u2010kinase inhibitors targeting VEGFR\u20102, EGFR, and HER\u20102 with IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.20, 0.21, and 0.19\u2009\u03bcM, respectively, and IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.67, 0.53, and 0.40\u2009\u03bcM, respectively, hence circumventing cancer resistance mechanisms. The most potent Compound\n                    <jats:bold>2h<\/jats:bold>\n                    prompted apoptosis and necrosis at % G0\u2010G1 phase in HCT\u2010116 via the activation of caspase\u20103 and 8, with significant downregulation of anti\u2010apoptotic protein Bcl\u20102. Additionally, Compound\n                    <jats:bold>2h<\/jats:bold>\n                    markedly suppressed immunomodulatory proteins TNF\u2010\u03b1 and IL\u20106 levels by 80.9% and 88.2%, respectively, in comparison to dexamethasone (82.7% and 93.2%, respectively), which attenuates tumor\u2010promoting inflammation, disrupting pro\u2010survival signaling pathways and metastasis. In silico ADMET, toxicity, and molecular docking studies were performed; notably, the docking simulations generated an interesting hypothesis for potential direct binding to Bcl\u20102, an effect distinct from the experimentally observed downstream downregulation of its expression. The present results pave the way for further developing of\n                    <jats:bold>2h<\/jats:bold>\n                    candidate as a multi\u2010tyrosine kinases inhibitor toward colon cancer cells.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70314","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:18:58Z","timestamp":1778570338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pyrimidine\u2010Derived Scaffolds Targeting VEGFR\u20102, EGFR, and HER\u20102: Synthesis, Anticancer\/Immunomodulatory Evaluation, and In Silico Analysis"],"prefix":"10.1002","volume":"87","author":[{"given":"Naglaa M.","family":"Ahmed","sequence":"first","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department Faculty of Pharmacy, Capital University (Formerly Helwan University), Ain\u2010Helwan Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Gaballah","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department Faculty of Pharmacy, Capital University (Formerly Helwan University), Ain\u2010Helwan Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belen","family":"Altava","sequence":"additional","affiliation":[{"name":"Department of Inorganic and Organic Chemistry ESTCE, Universitat Jaume I Castell\u00f3n Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H.","family":"Lotfallah","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy, El Saleheya El Gadida University El Saleheya El Gadida Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4MD00927A"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.22638"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.9734\/jpri\/2020\/v32i2430780"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.202000351"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.202100359"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2021.116384"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.4c04853"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-443-18677-6.00012-9"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-023-10245-3"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0804-2"},{"key":"e_1_2_11_12_1","first-page":"360","article-title":"Synthesis of 3,4\u2010Dihydropyrimidin\u20102(1H)\u2010Ones","volume":"23","author":"Biginelli P.","year":"1893","journal-title":"Gazzetta Chimica Italiana"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10304-4"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.54.3298"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0341-y"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(08)70285-7"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2023.2222172"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01592-13"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-38403-1"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27196044"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-023-02475-z"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.02.047"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2022.105770"},{"issue":"46","key":"e_1_2_11_26_1","first-page":"141","article-title":"Synthesis of Some New Thiouracil Derivatives With Expected Biological Activity","volume":"32","author":"Fathalla O. 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