Tuesday, August 26, 2025

Potent Inducers of Paraptosis through Electronic Tuning of Hemicyanine Electrophiles

uan F. Tamez-Fernández, Craig F. Steven, Jade Nguyen, and Pablo Rivera-Fuentes

Journal of the American Chemical Society 2025

DOI: 10.1021/jacs.5c07109

Paraptosis is a distinct form of programmed cell death characterized by cytoplasmic vacuolization, mitochondrial swelling, and endoplasmic reticulum (ER) dilation, offering an alternative to apoptosis for therapeutic applications. In this study, we identified a hemicyanine derivative that is a potent paraptosis inducer in two cancer cell lines. This compound triggers hallmark paraptotic features, including ER swelling, mitochondrial morphological changes, increased superoxide production, and caspase-independent cell death. This activity is dependent on the ability of the probe to modify thiols covalently. Proteomic analysis using a biotinylated, activity-based probe revealed Sec23 homologue A and GDP-dissociation inhibitor alpha as potential targets implicated in paraptosis activation. This lead compound already displayed some degree of selectivity, exemplified by its minimal interaction with well-known nucleophilic protein targets such as protein disulfide isomerases. These findings establish the hemicyanine chemical family as a promising scaffold for paraptosis research and suggest potential as a therapeutic lead for diseases where traditional apoptosis pathways are dysregulated.

A multicenter, open-label, first-in-human study of TYRA-200 in advanced intrahepatic cholangiocarcinoma and other solid tumors with activating FGFR2 gene alterations (SURF201).

Jordi Rodon Ahnert ,  Sameek Roychowdhury ,  Haley Ellis ,  Fernando F. Blanco ,  Timothy Burn ,  Jennifer Michelle Davis ,  Alex Balcer ,  ...