Novel Pyrazolo [1,5-a]-1,3,5-Triazine Derivatives as CDK7 Inhibitors: Synthesis and Biological Insights in Pancreatic
Daniela Carbone1, Francesca Terrana1, Ludovica Sciuto2
1Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze Ed.16, 90128, Palermo, Italy.
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.
Insights
New pyrazolo[1,5-a]-1,3,5-triazine derivatives show potent anticancer activity against pancreatic ductal adenocarcinoma (PDAC). These compounds inhibit cyclin-dependent kinase 7 (CDK7), induce apoptosis, and reduce tumor cell viability.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options.
- Cyclin-dependent kinase 7 (CDK7) is a promising therapeutic target in PDAC due to its role in gene transcription and cell cycle regulation.
Purpose of the Study:
- To synthesize and evaluate novel indolyl and 7-aza-indolyl pyrazolo[1,5-a]-1,3,5-triazine derivatives as potential CDK7 inhibitors for PDAC treatment.
- To assess the antiproliferative and anti-migratory effects of these compounds in PDAC cell lines and preclinical models.
Main Methods:
- Synthesis of 33 novel pyrazolo[1,5-a]-1,3,5-triazine derivatives.
- Screening for antiproliferative and cell migration inhibition activity against PDAC cell lines (SUIT 2.28, PATU-T, PANC-1).
- Evaluation of lead compounds in gemcitabine-resistant and primary PDAC cells, spheroidal cultures, and assessment of apoptosis and gene expression.
Main Results:
- Eight out of 33 derivatives exhibited significant cytotoxicity (IC50: 0.19–1.58 µM) and inhibited cell migration within 4-24 hours.
- The two most potent compounds demonstrated activity in gemcitabine-resistant and primary PDAC models.
- These compounds induced apoptosis, upregulated apoptotic gene expression, disrupted the cell cycle, and reduced viability in spheroidal cultures, while effectively inhibiting CDK7.
Conclusions:
- Novel pyrazolo[1,5-a]-1,3,5-triazine derivatives are effective inhibitors of CDK7 and exhibit potent anticancer activity against PDAC.
- These compounds represent promising candidates for further development as therapeutic agents for pancreatic cancer, including gemcitabine-resistant forms.
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