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Rationally engineered IR-783 octanoate as an enzyme-activatable fluorogenic tool for functional imaging of h Notum in living systems
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作者 Lilin Song Mengru Sun +9 位作者 Yuqing Song Feng Zhang Bei Zhao Hairong Zeng Jinhui Shi Huixin Liu Shanshan Zhao Tian Tian Heng Yin Guangbo Ge 《Chinese Chemical Letters》 SCIE CAS CSCD 2024年第11期442-447,共6页
As a vital negative regulator of Wnt signaling pathway,human Notum(hNotum)plays a crucial regulatory role in the progression of many human diseases.Deciphering the relevance of h Notum to human diseases requires pract... As a vital negative regulator of Wnt signaling pathway,human Notum(hNotum)plays a crucial regulatory role in the progression of many human diseases.Deciphering the relevance of h Notum to human diseases requires practical and reliable tools for visualizing h Notum activity in living systems.Herein,an enzyme-activatable fluorogenic tool(IR-783 octanoate)was rationally engineered for sensing and imaging h Notum activity in living systems by integrating computer-aided molecular design and biochemical assays.IR-783 octanoate showed good optical properties,excellent specificity and high binding-affinity towards h Notum(K_(m)=0.98μmol/L).IR-783 octanoate could be well up-taken into the cancerous cells or tumors that over-expressed organic anion transporting polypeptides(OATPs),and then hydrolyzed by cellular h Notum to release free IR-783 ketone,which created brightly fluorescent signals around 646 nm.Further investigations showed that IR-783 octanoate achieved a good performance for in-situ functional imaging of h Notum in both living cells,cancerous tissues and organs.It was also found that some SW620cells with multipolar spindles could be stained by IR-783 octanoate to emit extremely bright signals,suggesting that this agent could be used as a novel visualizing tool for tracing the cells undergoing abnormal cell mitoses.Collectively,this study devises a highly specific fluorogenic tool for in-situ functional imaging of hNotum in living systems,which offers a practical and reliable tool to dynamically track the changes in h Notum activity under various conditions. 展开更多
关键词 hnotum Optical substrate Computer-aided molecular design In-situ functional imaging Cancer diagnosis
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Chalcone derivatives as novel,potent and selective inhibitors against human Notum:Structure–activity relationships and biological evaluations
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作者 Jin-Hui Shi Bei Zhao +7 位作者 Li-Lin Song Yu-Qing Song Meng-Ru Sun Tian Tian Hong-Yu Chen Yun-Qing Song Jian-Ming Sun Guang-Bo Ge 《Chinese Chemical Letters》 SCIE CAS CSCD 2024年第3期321-325,共5页
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 ... 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(IC_(50)=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(5μmol/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. 展开更多
关键词 Human notum(hnotum) CHALCONE Computer-assisted drug discovery Structure–activity relationship(SAR) Anti-colorectal cancer agent
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