Chalcone derivatives as novel, potent and selective inhibitors against human Notum: Structure-activity relationships and biological evaluations

Human Notum (hNotum) inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer. Herein, two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors. Structure-activity relationship (SAR) studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect, while 4' ethoxyl and 3' -alkyl substitutions on B-ring were beneficial for hNotum inhibition. Among all tested chalcones, B11 displayed the most potent anti-Notum effect (IC50 = 3.6 nmol/L), good selectivity, excellent chemical stability and suitable metabolic stability. Further investigations showed that B11 acted as a competitive inhibitor of hNotum, while this agent (5 mu mol/L) significantly weaken the migration abilities of colorectal cancer cells. Collectively, this study deciphers the SARs of chalcones as hNotum inhibitors and reports a novel and potent hNotum inhibitor with the anti-migration effect on colorectal cancer cells, which offers a promising lead compound to develop novel anti-cancer agents. (c) 2024 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.