Front Cover: Synthesis of Unsymmetrical Squaramides as Allosteric GSK‐3β Inhibitors Promoting β‐Catenin‐Mediated Transcription of TCF/LEF in Retinal Pigment Epithelial Cells (ChemMedChem 24/2022)

Abstract

The Front Cover shows the sustainable approach used to develop new unsymmetrical squaramides acting as allosteric GSK3β inhibitors, promoting TCF‐LEF transcription in retinal pigment epithelial ARPE‐19 cells. This work highlights how green chemistry coupled with computational and biological studies could be a valuable strategy for developing interesting pharmacological tools, activating neuroprotective pathways, and useful in retinal diseases associated with inflammatory/oxidative damage. More information can be found in the Research Article by Gabriele Carullo, Stefania Butini et al.

GSK-3β Allosteric Inhibition: A Dead End or a New Pharmacological Frontier?

“…Recently, Carullo and colleagues proposed a new class of asymmetric squaramides as GSK-3β inhibitors [ 101 ]. This family of compounds was studied in vitro by testing their inhibitory effect on GSK-3β activity.…”

“…Finally, 6j was tested for its toxicity and inhibition of GSK-3β in retinal pigment epithelium (RPE) cells. From these analyses, 6j induced significant cell toxicity at 100 μM, and had significant inhibitory effects on the pathway downstream of GSK-3β at 2.5 μM [ 101 ]. These preliminary evaluations suggest 6j is a candidate for future development as a novel allosteric GSK-3β inhibitor.…”