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N‑Biphenyl Pyrrolinones andnDibenzofurans as RNA-Binding Protein LIN28 Inhibitors Disrupting thenLIN28–Let‑7 Interaction 联苯吡咯啉酮和二苯并呋喃作为rna结合蛋白LIN28抑制剂，破坏了nLIN28 -&lt；i>Let - 7</i&gt

Figshare Pub Date : 2023-11-14 DOI: 10.1021/acsmedchemlett.3c00341.s001

Lydia Borgelt (9426918), Lisa Hohnen (17388337), Jakob S. Pallesen (7313471), Pascal Hommen (10213128), Georg L. Goebel (10213134), Francesco Bosica (4397542), Yang Liu (4829), Gavin O’Mahony (2300806), Peng Wu (210686)

{"title":"N‑Biphenyl Pyrrolinones andnDibenzofurans as RNA-Binding Protein LIN28 Inhibitors Disrupting thenLIN28–Let‑7 Interaction","authors":"Lydia Borgelt (9426918), Lisa Hohnen (17388337), Jakob S. Pallesen (7313471), Pascal Hommen (10213128), Georg L. Goebel (10213134), Francesco Bosica (4397542), Yang Liu (4829), Gavin O’Mahony (2300806), Peng Wu (210686)","doi":"10.1021/acsmedchemlett.3c00341.s001","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.3c00341.s001","url":null,"abstract":"The RNA-binding proteinnLIN28 is a regulator of miRNA let-7 biogenesis. Inhibitorsnof LIN28 are highly sought after given thencentral role that LIN28 plays in tumorigenesis and development ofncancer stem cells as well as LIN28’s association with poornclinical prognosis. Although LIN28 inhibitors of different scaffoldsnhave been reported, the potential of most LIN28 inhibiting small moleculesnwas not fully explored since very limited structure–activitynrelationship (SAR) studies have been performed. We previously identifiedntrisubstituted pyrrolinones as a new class of LIN28 inhibitors disruptingnthe LIN28–let-7 interaction. Here, we performednextensive SAR by evaluating 95 small molecules and identified newntrisubstituted pyrrolinones featuring either an N-biphenyl or N-dibenzofuran substituent, overthrowingnthe existing conclusion that a salicylic acid moiety is indispensablenfor activity. Exchange of the negatively charged salicylic acid moietynin LIN28 inhibitors with a heterocyclic substituent is beneficialnfor membrane permeability, leading to increased activity in a cellularnassay, and will potentially reduce toxicity.","PeriodicalId":522816,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147904195","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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