{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:16:22Z","timestamp":1777860982506,"version":"3.51.4"},"reference-count":31,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"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                    Chronic myeloid leukemia treatment faces the challenge of resistance to BCR\u2010ABL1 tyrosine kinase inhibitors. To address this, we rationally designed six new imatinib\u2010derived compounds\n                    <jats:bold>2(a\u2013f)<\/jats:bold>\n                    by replacing the quinoline moiety with a [1,2,4]triazolo[1,5\u2010\n                    <jats:italic>a<\/jats:italic>\n                    ]pyrimidine scaffold via classical bioisosterism. The compounds were efficiently synthesized and characterized. Biological evaluation revealed that compound\n                    <jats:bold>2a<\/jats:bold>\n                    exhibited cytotoxic activity in BCR\u2010ABL1\u2010positive K562 cells (47% viability inhibition at 10 \u00b5M, IC\n                    <jats:sub>50<\/jats:sub>\n                    = 9.7 \u00b5M). However, enzymatic assays demonstrated that\n                    <jats:bold>2a<\/jats:bold>\n                    does not directly inhibit the wild\u2010type ABL1 kinase, unlike IMT. This finding, coupled with its cytotoxicity in nontumorigenic WSS\u20101 cells, indicates an alternative, off\u2010target mechanism. A clear structure\u2013activity relationship identified the detrimental effect of a \u2010CF\n                    <jats:sub>3<\/jats:sub>\n                    substitution. Overall, this work applies bioisosteric replacement to generate a new chemotype and uncovers a mechanistically divergent lead. The distinct, ABL1\u2010independent mechanism of compound\n                    <jats:bold>2a<\/jats:bold>\n                    establishes a solid foundation for future optimization and highlights its potential as a starting point for developing novel antimyeloproliferative agents with a different therapeutic profile.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202501100","type":"journal-article","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T20:59:55Z","timestamp":1776632395000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of [1,2,4]triazolo[1,5\u2010\n                    <i>a<\/i>\n                    ]pyrimidine\u2010Imatinib Hybrids With Selective Cytotoxic Activity: A Mechanistically Divergent Series From Direct BCR\u2010ABL1 Inhibition"],"prefix":"10.1002","volume":"21","author":[{"given":"Stefany Castro Bazan","family":"Moura","sequence":"first","affiliation":[{"name":"Laboratorio de Sintese de Farmacos Instituto de Tecnologia em Farmacos\u2010Farmanguinhos  Rio de Janeiro Brazil"},{"name":"Programa de Pos\u2010gradua\u00e7\u00e3o em Farmacologia e Quimica Medicinal Instituto de Ciencias Biomedicas Centro de Ciencias da Saude  Rio de Janeiro Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andressa Paula","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Laboratorio de Sintese de Farmacos Instituto de Tecnologia em Farmacos\u2010Farmanguinhos  Rio de Janeiro Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joao de Mello Rezende","family":"Neto","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioquimica Experimental e Computacional de Farmacos Instituto Oswaldo Cruz  Rio de Janeiro Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael 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Nascimento","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Laboratorio de Sintese de Farmacos Instituto de Tecnologia em Farmacos\u2010Farmanguinhos  Rio de Janeiro Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debora Inacio","family":"Leite","sequence":"additional","affiliation":[{"name":"Laboratorio de Sintese de Farmacos Instituto de Tecnologia em Farmacos\u2010Farmanguinhos  Rio de Janeiro Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daiane Vitoria","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laboratorio de Sintese de Farmacos Instituto de Tecnologia em Farmacos\u2010Farmanguinhos  Rio de Janeiro Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica Macedo","family":"Bastos","sequence":"additional","affiliation":[{"name":"Laboratorio de Sintese de Farmacos Instituto de Tecnologia em Farmacos\u2010Farmanguinhos  Rio de Janeiro Brazil"},{"name":"Programa de 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