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Design, Synthesis,nand Biological Evaluation of Novel Allosteric Protein Disulfide IsomerasenInhibitors 新型变构蛋白二硫异构酶抑制剂的设计、合成及生物学评价

Figshare Pub Date : 2019-04-02 DOI: 10.1021/acs.jmedchem.8b01951.s007

Suhui Yang (1451101), Andrea Shergalis (6502606), Dan Lu (135836), Anahita Kyani (6542321), Ziwei Liu (1877539), Mats Ljungman (36206), Nouri Neamati (275633)

{"title":"Design, Synthesis,nand Biological Evaluation of Novel Allosteric Protein Disulfide IsomerasenInhibitors","authors":"Suhui Yang (1451101), Andrea Shergalis (6502606), Dan Lu (135836), Anahita Kyani (6542321), Ziwei Liu (1877539), Mats Ljungman (36206), Nouri Neamati (275633)","doi":"10.1021/acs.jmedchem.8b01951.s007","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.8b01951.s007","url":null,"abstract":"Proteinndisulfide isomerase (PDI) is responsible for nascent protein foldingnin the endoplasmic reticulum (ER) and is critical for glioblastomansurvival. To improve the potency of lead PDI inhibitor BAP2 ((E)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzonitrile),nwe designed and synthesized 67 analogues. We determined thatnPDI inhibition relied on the A ring hydroxyl group of the chalconenscaffold and cLogP increase in the sulfonamide chain improved potency.nDocking studies revealed that BAP2 and analogues bindnto His256 in the b′ domain of PDI, and mutation of His256 tonAla abolishes BAP2 analogue activity. BAP2 and optimized analogue 59 have modest thiol reactivity;nhowever, we propose that PDI inhibition by BAP2 analoguesndepends on the b′ domain. Importantly, analogues inhibit glioblastomancell growth, induce ER stress, increase expression of G2M checkpointnproteins, and reduce expression of DNA repair proteins. Cumulatively,nour results support inhibition of PDI as a novel strategy to treatnglioblastoma.","PeriodicalId":523705,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147920536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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