{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:42:34Z","timestamp":1781628154734,"version":"3.54.5"},"reference-count":54,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009794","name":"Breast Cancer Now","doi-asserted-by":"publisher","award":["2019AugSF1310"],"award-info":[{"award-number":["2019AugSF1310"]}],"id":[{"id":"10.13039\/100009794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001596","name":"IRCSET","doi-asserted-by":"publisher","award":["IRCLA\/2022\/2822"],"award-info":[{"award-number":["IRCLA\/2022\/2822"]}],"id":[{"id":"10.13039\/501100001596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"FAPERJ","doi-asserted-by":"publisher","award":["SEI\u2010260003\/006052\/2024"],"award-info":[{"award-number":["SEI\u2010260003\/006052\/2024"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004586","name":"FAPERJ","doi-asserted-by":"publisher","award":["260003\/004503\/2025"],"award-info":[{"award-number":["260003\/004503\/2025"]}],"id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,4,28]]},"abstract":"<jats:p>\n                    Breast cancer is the most frequently diagnosed malignancy and a leading cause of cancer\u2010related mortality among women worldwide. Triple\u2010negative breast cancer (TNBC) poses a major clinical challenge due to its aggressive nature, limited therapeutic options, and high propensity for drug resistance. Dysregulation of the phosphatidylinositol 3\u2010kinase (PI3K)\/AKT\/mTOR and histone deacetylase (HDAC) signaling pathways has been implicated in TNBC progression and therapeutic resistance, highlighting their potential as combinatorial targets. In this study, we report the design, synthesis, and biological evaluation of a novel series of triazine\u2010based multitarget inhibitors aimed at the dual inhibition of PI3K and HDAC. Among the synthesized compounds,\n                    <jats:bold>5b<\/jats:bold>\n                    and\n                    <jats:bold>5f<\/jats:bold>\n                    demonstrated the most promising profiles, exhibiting low nanomolar IC\n                    <jats:sub>50<\/jats:sub>\n                    values against HDAC6 (2.33 and 6.02\u2009nM) and PI3K\u03b1 (17.5 and 236\u2009nM), respectively. Both compounds reduced cell viability in breast cancer cell lines, with IC\n                    <jats:sub>50<\/jats:sub>\n                    values below 5\u2009\u00b5M in MDA\u2010MB\u2010231 cells. Western blot analysis confirmed inhibition of HDAC and PI3K signaling in treated cells. Molecular docking and dynamics simulations further revealed stable binding modes and favorable interactions within the active sites of both targets. Overall,\n                    <jats:bold>5b<\/jats:bold>\n                    and\n                    <jats:bold>5f<\/jats:bold>\n                    represent promising lead candidates for further optimization toward the development of novel dual HDAC\/PI3K inhibitors with potential application in TNBC therapy, as evaluated in TNBC\u2010relevant models.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202501041","type":"journal-article","created":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T06:10:01Z","timestamp":1777183801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design, Synthesis, and Biological Evaluation of Novel Triazine\u2010Based Dual Histone Deacetylase\/phosphatidylinositol 3\u2010kinase Inhibitors for Breast Cancer Therapy"],"prefix":"10.1002","volume":"21","author":[{"given":"Lara","family":"Luzietti","sequence":"first","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences (PBS) Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Salgado","family":"Pires","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Avalia\u00e7\u00e3o e S\u00edntese de Subst\u00e2ncias Bioativas (LASSBio) Instituto de Ci\u00eancias Biom\u00e9dicas Universidade Federal do Rio de Janeiro Cidade Universit\u00e1ria  Rio de Janeiro Brazil"},{"name":"Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Farmacologia e Qu\u00edmica Medicinal (PPGFQM) Instituto de Ci\u00eancias Biom\u00e9dicas Universidade Federal do Rio de Janeiro Cidade Universit\u00e1ria  Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ryan","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences (PBS) Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crisamie","family":"Regidor","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences (PBS) Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Hiller","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danilo","family":"Sarti","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences (PBS) Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tr\u00edona","family":"N\u00ed Chonghaile","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro de Sena Murteira","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Avalia\u00e7\u00e3o e S\u00edntese de Subst\u00e2ncias Bioativas (LASSBio) Instituto de Ci\u00eancias Biom\u00e9dicas Universidade Federal do Rio de Janeiro Cidade Universit\u00e1ria  Rio de Janeiro Brazil"},{"name":"Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Farmacologia e Qu\u00edmica Medicinal (PPGFQM) Instituto de Ci\u00eancias Biom\u00e9dicas Universidade Federal do Rio de Janeiro Cidade Universit\u00e1ria  Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1000-0357","authenticated-orcid":false,"given":"Damir","family":"Vare\u0161lija","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences (PBS) Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7898-7093","authenticated-orcid":false,"given":"Daniel Alencar","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences (PBS) Royal College of Surgeons in Ireland  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"World Health Organization Breast Cancer accessed on 21 Oct2025 https:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/breast\u2010cancer."},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/BCTT.S432526"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-022-00468-0"},{"key":"e_1_2_11_5_1","first-page":"5155","article-title":"Chemoresistance In Breast Cancer: Pi3k\/akt Pathway Inhibitors Vs The Current Chemotherapy","volume":"11","author":"Kaboli P. 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