Jelena Bozilovic , Lorenz Eing , Benedict-Tilman Berger , Bikash Adhikari , Janik Weckesser , Nicola B. Berner , Stephanie Wilhelm , Bernhard Kuster , Elmar Wolf , Stefan Knapp
{"title":"靶向AURORA-A激酶的新型高效PROTAC","authors":"Jelena Bozilovic , Lorenz Eing , Benedict-Tilman Berger , Bikash Adhikari , Janik Weckesser , Nicola B. Berner , Stephanie Wilhelm , Bernhard Kuster , Elmar Wolf , Stefan Knapp","doi":"10.1016/j.crchbi.2022.100032","DOIUrl":null,"url":null,"abstract":"<div><p>The family of AURORA kinases is essential for cell cycle progression and dysregulation of AURORA-A in cancer led to a large number of clinical and pre-clinical inhibitors. However, ATP competitive AURORA-A inhibitors usually do not target non-catalytic functions that have also been identified as mechanisms promoting tumorigenesis. To target non-catalytic as well as catalytic functions, we developed a series of PROTACs (PROteolysis TArgeting Chimeras) based on the selective AURORA-A kinase inhibitor MK-5108 (VX-689) and the CEREBLON E3-ligase ligand thalidomide. The most potent PROTAC, JB301, had good physicochemical properties and cell penetration resulting in degradation of AURORA-A in leukemic cells at single digit nM concentration.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100032"},"PeriodicalIF":0.0000,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666246922000143/pdfft?md5=fb3ff5b1283825abf31075b23d9e673f&pid=1-s2.0-S2666246922000143-main.pdf","citationCount":"8","resultStr":"{\"title\":\"Novel, highly potent PROTACs targeting AURORA-A kinase\",\"authors\":\"Jelena Bozilovic , Lorenz Eing , Benedict-Tilman Berger , Bikash Adhikari , Janik Weckesser , Nicola B. Berner , Stephanie Wilhelm , Bernhard Kuster , Elmar Wolf , Stefan Knapp\",\"doi\":\"10.1016/j.crchbi.2022.100032\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The family of AURORA kinases is essential for cell cycle progression and dysregulation of AURORA-A in cancer led to a large number of clinical and pre-clinical inhibitors. However, ATP competitive AURORA-A inhibitors usually do not target non-catalytic functions that have also been identified as mechanisms promoting tumorigenesis. To target non-catalytic as well as catalytic functions, we developed a series of PROTACs (PROteolysis TArgeting Chimeras) based on the selective AURORA-A kinase inhibitor MK-5108 (VX-689) and the CEREBLON E3-ligase ligand thalidomide. The most potent PROTAC, JB301, had good physicochemical properties and cell penetration resulting in degradation of AURORA-A in leukemic cells at single digit nM concentration.</p></div>\",\"PeriodicalId\":72747,\"journal\":{\"name\":\"Current research in chemical biology\",\"volume\":\"2 \",\"pages\":\"Article 100032\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2666246922000143/pdfft?md5=fb3ff5b1283825abf31075b23d9e673f&pid=1-s2.0-S2666246922000143-main.pdf\",\"citationCount\":\"8\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current research in chemical biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2666246922000143\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current research in chemical biology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666246922000143","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
The family of AURORA kinases is essential for cell cycle progression and dysregulation of AURORA-A in cancer led to a large number of clinical and pre-clinical inhibitors. However, ATP competitive AURORA-A inhibitors usually do not target non-catalytic functions that have also been identified as mechanisms promoting tumorigenesis. To target non-catalytic as well as catalytic functions, we developed a series of PROTACs (PROteolysis TArgeting Chimeras) based on the selective AURORA-A kinase inhibitor MK-5108 (VX-689) and the CEREBLON E3-ligase ligand thalidomide. The most potent PROTAC, JB301, had good physicochemical properties and cell penetration resulting in degradation of AURORA-A in leukemic cells at single digit nM concentration.
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