Work

Potent Caspase‐1 Antagonists From Dihydropyridine Derivatives: In Vitro Fluorescence Assays and Cell Imaging

Year: 2026

Type: article

Abstract: Caspase‐1 is a key marker in pyroptosis and inflammation, playing a central role in the pathogenesis of various acute and chronic inflammatory diseases. While some caspase‐1 sensing and inhibition studies have been reported, the use of DHPs for these applications remains unexplored. To address this challenge, a novel fluorescent compound, zWEHD‐NH‐DHP , was synthesized and subsequently developed as a real‐time caspase‐1 detection in vitro and in cells. Furthermore, a new class of potential caspase‐1 inhibitors was investigated through the screening of a series of nonfluorogenic DHPs, utilizing our established caspase‐1 fluorescent sensing system. Among the tested compounds, THD and FD showed caspase‐1 inhibition with IC 50 values of 2.8 ± 0.1 nM and 3.2 ± 0.1 µM, respectively. THD , which exhibited comparable potency to the well‐known inhibitor VX‐765 (3.68 nM), was selected for further investigation. Moreover, a competitive inhibition mechanism of THD at the enzyme's active site was supported by molecular docking and MD simulations. Western blot analysis of PMA‐differentiated THP‐1 cells further supported this observation by showing reduced cleaved IL‐1β levels in the presence of THD . This inhibitory effect of THD on caspase‐1 activity in a complex cell system was further confirmed by the concentration‐dependent morphological changes in BMDMs.

Source: ChemMedChem

DOI: 10.1002/cmdc.70496