Andreas Krämer , Amelie Tjaden , Benardina Ndreshkjana , Claudia Tredup , Henner F. Farin , Stefan Knapp , Yves L. Janin , Susanne Müller
{"title":"IPP/CNRS-A017:人二氢乙酸脱氢酶(hDHODH)化学探针","authors":"Andreas Krämer , Amelie Tjaden , Benardina Ndreshkjana , Claudia Tredup , Henner F. Farin , Stefan Knapp , Yves L. Janin , Susanne Müller","doi":"10.1016/j.crchbi.2022.100034","DOIUrl":null,"url":null,"abstract":"<div><p>Human Dihydroorotate dehydrogenase, which catalyses <em>de novo</em> pyrimidine biosynthesis, is an emerging target for treatment of infectious diseases, arthritis and cancer. In order to provide a chemical tool studying this key enzyme, we characterized IPP/CNRS-A017, a highly potent, selective, and cell-active inhibitor of the human Dihydroorotate dehydrogenase (hDHODH). In this report, we describe the crystal structure of IPP/CNRS-A017 in complex with hDHODH, providing inside into its binding mode. Additionally, further off-target profiling in a kinome-wide screen and a G-Protein-Coupled Receptors screen as well as investigated cell viability effects in three different cell lines (HEK293T, U2OS, human fibroblasts) confirmed that IPP/CNRS-A017 is a highly selective chemical tool to study the biology of hDHODH. Specific sensitivity to IPP/CNRS-A017 was observed in patient-derived colorectal cancer organoids.</p></div>","PeriodicalId":72747,"journal":{"name":"Current research in chemical biology","volume":"2 ","pages":"Article 100034"},"PeriodicalIF":0.0000,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666246922000167/pdfft?md5=28ed6a7280dd9ccb2c5b183cec69e0fa&pid=1-s2.0-S2666246922000167-main.pdf","citationCount":"0","resultStr":"{\"title\":\"IPP/CNRS-A017: A chemical probe for human dihydroorotate dehydrogenase (hDHODH)\",\"authors\":\"Andreas Krämer , Amelie Tjaden , Benardina Ndreshkjana , Claudia Tredup , Henner F. Farin , Stefan Knapp , Yves L. Janin , Susanne Müller\",\"doi\":\"10.1016/j.crchbi.2022.100034\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Human Dihydroorotate dehydrogenase, which catalyses <em>de novo</em> pyrimidine biosynthesis, is an emerging target for treatment of infectious diseases, arthritis and cancer. In order to provide a chemical tool studying this key enzyme, we characterized IPP/CNRS-A017, a highly potent, selective, and cell-active inhibitor of the human Dihydroorotate dehydrogenase (hDHODH). In this report, we describe the crystal structure of IPP/CNRS-A017 in complex with hDHODH, providing inside into its binding mode. Additionally, further off-target profiling in a kinome-wide screen and a G-Protein-Coupled Receptors screen as well as investigated cell viability effects in three different cell lines (HEK293T, U2OS, human fibroblasts) confirmed that IPP/CNRS-A017 is a highly selective chemical tool to study the biology of hDHODH. Specific sensitivity to IPP/CNRS-A017 was observed in patient-derived colorectal cancer organoids.</p></div>\",\"PeriodicalId\":72747,\"journal\":{\"name\":\"Current research in chemical biology\",\"volume\":\"2 \",\"pages\":\"Article 100034\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2666246922000167/pdfft?md5=28ed6a7280dd9ccb2c5b183cec69e0fa&pid=1-s2.0-S2666246922000167-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current research in chemical biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2666246922000167\",\"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/S2666246922000167","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
IPP/CNRS-A017: A chemical probe for human dihydroorotate dehydrogenase (hDHODH)
Human Dihydroorotate dehydrogenase, which catalyses de novo pyrimidine biosynthesis, is an emerging target for treatment of infectious diseases, arthritis and cancer. In order to provide a chemical tool studying this key enzyme, we characterized IPP/CNRS-A017, a highly potent, selective, and cell-active inhibitor of the human Dihydroorotate dehydrogenase (hDHODH). In this report, we describe the crystal structure of IPP/CNRS-A017 in complex with hDHODH, providing inside into its binding mode. Additionally, further off-target profiling in a kinome-wide screen and a G-Protein-Coupled Receptors screen as well as investigated cell viability effects in three different cell lines (HEK293T, U2OS, human fibroblasts) confirmed that IPP/CNRS-A017 is a highly selective chemical tool to study the biology of hDHODH. Specific sensitivity to IPP/CNRS-A017 was observed in patient-derived colorectal cancer organoids.
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