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Structure and activity based approach was used to synthesize derivatives: N(4)\u2010pyrrolidinyl (L1), N(4)\u2010piperidinyl (L2), N(4)\u2010morpholinyl (L3), N(4)\u2010methyl (L4), and N(4)\u2010ethyl (L5). The compounds were characterized by elemental analysis, FTIR,\n                    <jats:sup>1<\/jats:sup>\n                    H NMR,\n                    <jats:sup>13<\/jats:sup>\n                    C NMR, UV\u2010Vis spectroscopy, HRMS and single crystal X\u2010ray analysis. The antiproliferative activity of the synthesized TSCs was evaluated in a dose\u2010dependent manner against breast (MCF\u20107, MDA\u2010MB\u2010231), skin (A431), lung (A549, NCI\u2010H460), and prostate (PC3) cancer cell lines. L3 and L5 exhibited enhanced cytotoxicity in the low micromolar range of IC\n                    <jats:sub>50<\/jats:sub>\n                    ; 1.16\u20132.47\u2009\u00b5M. Notably, L5 showed superior potency in MCF\u20107 cells with IC\n                    <jats:sub>50<\/jats:sub>\n                    ; 1.16\u2009\u00b5M compared to the FDA\u2010approved thiosemicarbazone Triapine with IC\n                    <jats:sub>50<\/jats:sub>\n                    ; 4.27\u2009\u00b5M, while displaying minimal toxicity toward non\u2010tumorigenic MCF\u201010a breast epithelial cells with selectivity index &gt;\u200986.20, consistent with ADMET predictions. Molecular docking and molecular dynamics simulations demonstrated stronger binding affinity and greater complex stability of L5 with PTOV1 compared to the FDA approved drug Lenalidomide, supporting L5 drug likeness and therapeutic potential. Mechanistic investigations through functional assays like crystal violet assays, flow cytometry, immunoblotting, and microscopy revealed that L5 induces G0\/G1 cell\u2010cycle arrest, suppresses cell migration, invasion, colony formation, 3D spheroid growth, and promotes apoptotic cell death in MCF\u20107. Western blot analysis provided direct mechanistic evidence that L5 downregulates PTOV1 expression, leading to reduced phosphorylation of AKT1\/2\/3 and c\u2010Jun, reduced \u03b2\u2010catenin nuclear translocation, and decreased MMP\u20102 expression. L5 enhanced H2AX phosphorylation, suppressed PARP and BCL\u2010XL levels, and increased active caspase\u20103 driving L5 induced apoptosis. This study identifies L5 as a potent anticancer agent in breast cancer, acting through modulation of the PTOV1\u2010AKT\u2010\u03b2\u2010catenin signaling axis, and highlights PTOV1 as a promising therapeutic target.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70306","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:36:56Z","timestamp":1778481416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the Role of Novel N (4) Substituted 5,7\u2010Dibromoisatin Thiosemicarbazones in Modulating PTOV1 Activity for Therapeutic Relevance in Breast Cancer"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0519-5586","authenticated-orcid":false,"given":"Piyush","family":"Kumar","sequence":"first","affiliation":[{"name":"Faculty of Life Sciences and Biotechnology South Asian University Maidan Garhi New Delhi 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