Novel Pyrazolo [1,5-a]-1,3,5-Triazine Derivatives as CDK7 Inhibitors: Synthesis and Biological Insights in Pancreatic Ductal Adenocarcinoma Models.

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-25 DOI:10.1002/cmdc.202500448
Daniela Carbone, Francesca Terrana, Ludovica Sciuto, Camilla Pecoraro, Geng Xu, Stella Cascioferro, Girolamo Cirrincione, Godefridus J Peters, Elisa Giovannetti, Barbara Parrino, Patrizia Diana
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Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic tumor, is one of the most aggressive and lethal tumor types. Cyclin-dependent 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-aza-indolyl pyrazolo [1,5-a]-1,3,5-triazine derivatives are efficiently synthesized and screened for antiproliferative activity against three immortalized cell lines (SUIT 2.28, PATU-T, PANC-1) of PDAC. 8 out of 33 derivatives show remarkable cytotoxicity with IC50 values ranging from 0.19 to 1.58 µM 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-resistant and primary cells (PATU-T 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-T cultures. Additionally, both compounds effectively inhibit CDK7, as demonstrated by an enzyme-linked immunosorbent assay in cell extracts and by a specific enzymatic activity assay.

新型吡唑啉[1,5-a]-1,3,5-三嗪衍生物作为CDK7抑制剂:合成及其在胰腺导管腺癌模型中的生物学意义。
胰腺导管腺癌(Pancreatic ductal adencarcinoma, PDAC)是最常见的胰腺肿瘤,也是最具侵袭性和致死率的肿瘤类型之一。细胞周期蛋白依赖性激酶7 (Cyclin-dependent kinase 7, CDK7)最近被确定为多种人类和小鼠PDAC临床前肿瘤模型的一个有希望的靶点,因为它显著下调基因转录并优先抑制有丝分裂细胞周期。为了寻找新的CDK7抑制剂,我们高效合成了新的吲哚基和7-氮杂吲哚基吡唑啉[1,5-a]-1,3,5-三嗪衍生物,并对3种PDAC永生化细胞系(SUIT 2.28, PATU-T, PANC-1)进行了抗增殖活性筛选。33个衍生物中有8个显示出显著的细胞毒性,IC50值在0.19至1.58µM之间,并且从最早的时间点4小时开始显著抑制细胞迁移,持续到24小时。在临床相关模型中,包括吉西他滨耐药和原代细胞(PATU-T GR, PDAC3),进一步评估了两个最有效的化合物,证实了它们的有效活性。它们诱导细胞凋亡,上调凋亡基因表达,破坏细胞周期,显著降低球形PATU-T培养的活力。此外,这两种化合物都能有效抑制CDK7,正如细胞提取物中的酶联免疫吸附试验和特定酶活性试验所证明的那样。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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