{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:50:35Z","timestamp":1787795435584,"version":"build-2784847793"},"reference-count":62,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Blocking the p53\u2010MDM2 and\/or p53\u2010MDMX protein\u2212protein interaction (PPI) by small\u2010molecule inhibitors has been tracked as a potentially effective cancer treatment approach. Herein, we present the discovery of a new series of spirooxindole\u2010tethered pyrazolopyridine derivatives. The development of the new congeners was based on the analysis of the co\u2010crystal structures of the inhibitors bound to both MDM2 and MDMX and studying the binding interactions between the substituents of small molecules and the three subpockets of the p53\u2010MDM2\/MDMX. The spirooxindoles\n                    <jats:bold>6b<\/jats:bold>\n                    ,\n                    <jats:bold>6k<\/jats:bold>\n                    , and\n                    <jats:bold>6n<\/jats:bold>\n                    attained the most pronounced activity in the MULTI\u2010ARRAY MDM2\u2010p53 complex assay with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 1.26, 1.30, and 1.25\u2009\u00b5M, respectively, in comparison with nutlin\u20103 (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20092.03\u2009\u00b5M). The counterparts\n                    <jats:bold>6b<\/jats:bold>\n                    ,\n                    <jats:bold>6k<\/jats:bold>\n                    , and\n                    <jats:bold>6n<\/jats:bold>\n                    also revealed notable inhibitory potential against p53\u2010MDMX. The antiproliferative efficacy of the most active target compounds was assessed in HCT\u2010116 colon cancer cell line that overexpressed MDM2 and harbored wild\u2010type p53. The derivative\n                    <jats:bold>6k<\/jats:bold>\n                    accomplished the highest antiproliferative activity against HCT\u2010116 compared to nutlin\u20103. Moreover,\n                    <jats:bold>6k<\/jats:bold>\n                    displayed minimal toxicity compared to the reference nutlin\u20103 when examined on a normal cell line. Flow cytometric analysis revealed that\n                    <jats:bold>6k<\/jats:bold>\n                    controlled cell growth\n                    <jats:italic>via<\/jats:italic>\n                    cell cycle arrest at the G1 phase and induced cell death via apoptosis. Additionally, compound\n                    <jats:bold>6k<\/jats:bold>\n                    revealed a prominent effect in raising p53 levels with a 6.464\u2010fold increase compared to the control. Molecular docking and molecular dynamics simulations justified the observed efficacy. Collectively, this study showcased a new class of potent p53\u2010MDM2\/MDMX dual inhibitors possessing a spirooxindole scaffold which can be subjected to future development.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70277","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T05:22:51Z","timestamp":1775020971000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unlocking the Anticancer Potential of New Spirooxindoles via p53\u2010MDM2\/MDMX Dual Inhibition: In Vitro and In Silico Assessments"],"prefix":"10.1002","volume":"87","author":[{"given":"Haidy H.","family":"El\u2010Zoheiry","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab F.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud S.","family":"Elkotamy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Alsalam University Kafr El Zayat El Gharbeia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatem A.","family":"Abdel\u2010Aziz","sequence":"additional","affiliation":[{"name":"Department of Applied Organic Chemistry National Research Center Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada F.","family":"Elmasry","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm501541j"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2018.10.036"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28176428"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1039\/d6ra00037a"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2018.01.053"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.BIOORG.2022.106124"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-019-0362-7"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-03-0362"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01053"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605199"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01815"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.104748"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107766"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026618666180604080119"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114637"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.07.029"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.22079"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207116"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00900"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.25080\/Majora-629e541a-00e"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2024.107413"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.EJMECH.2021.113389"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-019-0937-4"},{"key":"e_1_2_7_26_1","doi-asserted-by":"crossref","unstructured":"Humphrey W. 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