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Aiming at developing an innovative class of allosteric inhibitors of GSK\u20103\u03b2 potentially useful for retinal degeneration, we explored the class of squaramides. The developed compounds (<jats:bold>6\u2009a<\/jats:bold>\u2013<jats:bold>l<\/jats:bold>) were obtained through a nontoxic one\u2010pot synthetic protocol, which employs low\u2010cost goods and avoids any purification step. Ethanol was used as the reaction solvent, simultaneously allowing the pure reaction products\u2032 recovery (by precipitation). Out of this set of squaramides, <jats:bold>6\u2009j<\/jats:bold> stood out, from computational and enzymatic converging data, as an ATP non\u2010competitive inhibitor of GSK\u20103\u03b2 of micromolar potency. When engaged in cellular studies using retinal pigment epithelial cells (ARPE\u201019) transfected with a luciferase reporter gene under the control of T\u2010cell factor\/lymphoid enhancer factor (TCF\/LEF) binding sites, <jats:bold>6\u2009j<\/jats:bold> was able to dose\u2010dependently induce \u03b2\u2010catenin nuclear accumulation, as shown by the increased luciferase activity at a concentration of 2.5\u2005\u03bcM.<\/jats:p>","DOI":"10.1002\/cmdc.202200456","type":"journal-article","created":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T08:46:30Z","timestamp":1664873190000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Synthesis of Unsymmetrical Squaramides as Allosteric GSK\u20103\u03b2 Inhibitors Promoting \u03b2\u2010Catenin\u2010Mediated Transcription of TCF\/LEF in Retinal Pigment Epithelial 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