Aliakbar Khalili Yazdi, Sumera Perveen, Xiaosheng Song, Aiping Dong, Magdalena Szewczyk, Matthew Calabrese, Agustin Casimiro-Garcia, Chakrapani Subramanyam, Matthew S Dowling, Emel Ficici, Jisun Lee, Justin I Montgomery, Thomas N O'Connell, Grzegorz J Skrzypek, Tuan P Tran, Matthew D Troutman, Feng Wang, Jennifer A Young, Jinrong Min, Dalia Barsyte-Lovejoy, Peter J Brown, Vijayaratnam Santhakumar, Cheryl Arrowsmith, Masoud Vedadi, Dafydd R Owen
{"title":"人类E3连接酶c端到LisH (CTLH)降解复合物Gid4亚基的化学工具","authors":"Aliakbar Khalili Yazdi, Sumera Perveen, Xiaosheng Song, Aiping Dong, Magdalena Szewczyk, Matthew Calabrese, Agustin Casimiro-Garcia, Chakrapani Subramanyam, Matthew S Dowling, Emel Ficici, Jisun Lee, Justin I Montgomery, Thomas N O'Connell, Grzegorz J Skrzypek, Tuan P Tran, Matthew D Troutman, Feng Wang, Jennifer A Young, Jinrong Min, Dalia Barsyte-Lovejoy, Peter J Brown, Vijayaratnam Santhakumar, Cheryl Arrowsmith, Masoud Vedadi, Dafydd R Owen","doi":"10.1101/2023.11.13.566858","DOIUrl":null,"url":null,"abstract":"We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"38 6","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chemical Tools for the Gid4 Subunit of the Human E3 Ligase C-terminal to LisH (CTLH) Degradation Complex\",\"authors\":\"Aliakbar Khalili Yazdi, Sumera Perveen, Xiaosheng Song, Aiping Dong, Magdalena Szewczyk, Matthew Calabrese, Agustin Casimiro-Garcia, Chakrapani Subramanyam, Matthew S Dowling, Emel Ficici, Jisun Lee, Justin I Montgomery, Thomas N O'Connell, Grzegorz J Skrzypek, Tuan P Tran, Matthew D Troutman, Feng Wang, Jennifer A Young, Jinrong Min, Dalia Barsyte-Lovejoy, Peter J Brown, Vijayaratnam Santhakumar, Cheryl Arrowsmith, Masoud Vedadi, Dafydd R Owen\",\"doi\":\"10.1101/2023.11.13.566858\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.\",\"PeriodicalId\":486943,\"journal\":{\"name\":\"bioRxiv (Cold Spring Harbor Laboratory)\",\"volume\":\"38 6\",\"pages\":\"0\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-11-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv (Cold Spring Harbor Laboratory)\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2023.11.13.566858\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv (Cold Spring Harbor Laboratory)","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2023.11.13.566858","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Chemical Tools for the Gid4 Subunit of the Human E3 Ligase C-terminal to LisH (CTLH) Degradation Complex
We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.
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