Isolation and characterization ofβ-transducin repeat-containing protein ligands screened using a high-throughput screening system

作     者：XINTONG LIU EMIKO SANADA JIANG LI XIAOMENG LI HIROYUKI OSADA NOBUMOTO WATANABE 

作者机构：Chemical Resource Development Research UnitRIKEN CSRSWakoSaitama351-0198Japan Department of RIKEN Molecular and Chemical SomatologyGraduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityBunkyokuTokyo113-8510Japan Bioprobe Application Research UnitRIKEN CSRSWakoSaitama351-0198Japan Chemical Biology Research GroupRIKEN CSRSWakoSaitama351-0198Japan Guangdong Engineering Research Center of Oral Restoration and ReconstructionAffiliated Stomatology Hospital of Guangzhou Medical UniversityGuangzhou510180China KingMed School of Laboratory MedicineGuangzhou Medical UniversityGuangzhou510182China Department of Pharmaceutical SciencesUniversity of ShizuokaSuruga-kuShizuoka422-8526Japan 

出 版 物：《Oncology Research》 (肿瘤学研究（英文）)

年 卷 期：2023年第31卷第5期

页      面：645-654页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 

基　　金：supported by research grants from the JSPS/MEXT KAKENHI(JP19H05302 and JP21H00295 to N.W.) the MOSTRIKEN Collaboration Project(2021YFE0108000 to J.L.and N.W.) 

主　　题：Ubiquitin F-box protein Chemical biology 

摘      要：β-transducin repeat-containing protein(β-TrCP)is an F-box protein subunit of the E3 Skp1-Cullin-F box(SCF)type ubiquitin-ligase complex,and provides the substrate specificity for the *** find potent ligands ofβ-TrCP useful for the proteolysis targeting chimera(PROTAC)system usingβ-TrCP in the future,we developed a high-throughput screening system for small moleculeβ-TrCP *** screened the chemical library utilizing the system and obtained several hit *** effects of the hit compounds on in vitro ubiquitination activity of SCFβ-TrCP1 and on downstream signaling pathways were *** compounds NPD5943,NPL62020-01,and NPL42040-01 inhibited the TNFα-induced degradation of IκBαand its phosphorylated ***,they inhibited the activation of the transcription activity of NF-κB,indicating the effective inhibition ofβ-TrCP by the hit compounds in ***,we performed an in silico analysis of the hit compounds to determine the important moieties of the hit *** groups of NPL62020-01 and NPL42040-01 and hydroxyl groups of NPD5943 created hydrogen bonds withβ-TrCP similar to those created by intrinsic target phosphopeptides ofβ-*** findings enhance our knowledge of useful small molecule ligands ofβ-TrCP and the importance of residues that can be ligands ofβ-TrCP.