Abstract
Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases includ-ing 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=3.6nmol/L),good selectivity,excel-lent 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.
基金项目
国家自然科学基金(82104281)
国家自然科学基金(81922070)
国家自然科学基金(81973286)
国家自然科学基金(81801818)
国家自然科学基金(82273897)
Shanghai Municipal Health Commission's TCM research project(2022CX005)
Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202004)
Threeyear Action Plan for Shanghai TCM Development and Inheritance Program(ZY2021-2023-0401)
NETL
NSTL
万方数据