{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T09:53:26Z","timestamp":1792403606019,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2025,10,6]]},"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic tumor, is one of the most aggressive and lethal tumor types. Cyclin\u2010dependent kinase 7 (CDK7) has been recently identified as a promising target in multiple human and mouse PDAC preclinical tumor models, due to significant downregulation of gene transcription and preferential inhibition of the mitotic cell cycle. With the aim of finding new CDK7 inhibitors, new indolyl and 7\u2010aza\u2010indolyl pyrazolo [1,5\u2010a]\u22121,3,5\u2010triazine derivatives are efficiently synthesized and screened for antiproliferative activity against three immortalized cell lines (SUIT 2.28, PATU\u2010T, PANC\u20101) of PDAC. 8 out of 33 derivatives show remarkable cytotoxicity with IC<jats:sub>50<\/jats:sub> values ranging from 0.19 to 1.58 \u00b5M and remarkable inhibition of cell migration from the earliest time point of 4 h, persisting until 24 h. The two most active compounds are further evaluated in clinically relevant models,including gemcitabine\u2010resistant and primary cells (PATU\u2010T GR, PDAC3), confirming their potent activity. They induce apoptosis, upregulate apoptotic gene expression, and disrupt the cell cycle, significantly reducing the viability of spheroidal PATU\u2010T cultures. Additionally, both compounds effectively inhibit CDK7, as demonstrated by an enzyme\u2010linked immunosorbent assay in cell extracts and by a specific enzymatic activity assay.<\/jats:p>","DOI":"10.1002\/cmdc.202500448","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T15:45:12Z","timestamp":1756136712000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Pyrazolo [1,5\u2010a]\u22121,3,5\u2010Triazine Derivatives as CDK7 Inhibitors: Synthesis and Biological Insights in Pancreatic Ductal Adenocarcinoma Models"],"prefix":"10.1002","volume":"20","author":[{"given":"Daniela","family":"Carbone","sequence":"first","affiliation":[{"name":"Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF) University of Palermo  Viale delle Scienze Ed.16 90128 Palermo 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