{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:26:09Z","timestamp":1785432369856,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Meinox, T\u00dcB\u0130TAK BiGG Technoinitiative Capital Support Program"},{"name":"Gilead Sciences International Hematology & Oncology Program"},{"name":"Istanbul Atlas University"},{"id":[{"id":"https:\/\/ror.org\/02jqzm779","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: MEIS proteins are essential homeobox transcription factors that play critical roles in development and have been increasingly implicated in oncogenesis, including breast cancer. Methods: In this study, we identified and characterized novel small-molecule MEIS2 inhibitors through in silico docking targeting the active region of the human MEIS2 homeobox domain. Lead candidates MEISi-2E, MEISi-3, and MEISi-4 were identified with binding energies ranging from \u22123.0 to \u22123.90 kcal\/mol. The inhibitory potential of these molecules was validated in vitro using a species-conserved MEIS-Luciferase Reporter construct containing the TGACAG targeted locus. Results: Our results demonstrate that MEISi-2E, MEISi-3, and MEISi-4 significantly suppress MEIS-driven luciferase activity and downregulate the expression of Meis1, Meis2, and downstream genes such as IL17RB, CDH1, EGR2, PAX6, and SERPINE1 while upregulating negative regulator TGIF1 and SOX3. In breast cancer cell lines, these inhibitors exhibited potent growth inhibition, with MEISi-3 showing an exceptional IC50 as low as 0.1 \u03bcM in SK-BR-3 cells. Mechanistic studies using flow cytometry revealed that these inhibitors induce dose-dependent apoptosis and necrosis. Importantly, the novel inhibitors showed minimal toxicity to healthy human dermal and MRC5 fibroblasts, suggesting a favorable safety profile. Conclusions: These findings establish these small molecules as promising therapeutic candidates for targeting MEIS2-dependent pathways in breast cancer.<\/jats:p>","DOI":"10.3390\/ph19060881","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Development of Novel Small-Molecule MEIS2 Inhibitors That Induce Cell Death in Breast Cancer Cells by Targeting the Homeobox Domain"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8096-6056","authenticated-orcid":false,"given":"Fatih","family":"Kocaba\u015f","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Atlas University, 34403 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birkan","family":"Girgin","sequence":"additional","affiliation":[{"name":"Department of Neuropharmacology, Graduate School of Medicine, Hokkaido University, Sapporo 060-0808, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve","family":"Uslu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children\u2019s Hospital, St. Petersburg, FL 33701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1192-9416","authenticated-orcid":false,"given":"P\u0131nar","family":"Siyah","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Pharmacy, Bahcesehir University, 34349 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4789-7180","authenticated-orcid":false,"given":"Arif","family":"Mermer","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Health Sciences, 34668 Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3906\/biy-2006-25","article-title":"Oncogenic and tumor suppressor function of MEIS and associated factors","volume":"44","author":"Girgin","year":"2020","journal-title":"Turk. 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