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

• Published in: Chinese chemical letters 2024-03, Vol.35 (3), p.108405, Article 108405
• Main Authors: Shi, Jin-Hui, Zhao, Bei, Song, Li-Lin, Song, Yu-Qing, Sun, Meng-Ru, Tian, Tian, Chen, Hong-Yu, Song, Yun-Qing, Sun, Jian-Ming, Ge, Guang-Bo
• Format: Article
• Language: English
• Subjects: Anti-colorectal cancer agent; Chalcone; Computer-assisted drug discovery; Human notum (hNotum); Structure–activity relationship (SAR)
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2023.108405

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 µmol/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. Following two rounds of screening and optimization, a chalcone derivative (B11) deriving from 4′‑methoxy chalcone (A1) was identified as a novel, potent and selective inhibitor of human Notum, which could suppress the invasion of colorectal cancer cells. [Display omitted]