Robin C. E. Deutscher, Christian Meyners, Maximilian L. Repity, Wisely Oki Sugiarto, Jürgen M Kolos, Edvaldo Maciel, Tim Heymann, Thomas M. Geiger, Felix Hausch, Stefan Knapp, Frederik Lermyte
{"title":"Discovery of fully synthetic FKBP12-mTOR molecular glues","authors":"Robin C. E. Deutscher, Christian Meyners, Maximilian L. Repity, Wisely Oki Sugiarto, Jürgen M Kolos, Edvaldo Maciel, Tim Heymann, Thomas M. Geiger, Felix Hausch, Stefan Knapp, Frederik Lermyte","doi":"10.1039/d4sc06917j","DOIUrl":null,"url":null,"abstract":"Molecular glues are a new drug modality with the potential to engage otherwise undruggable targets. However, the rational discovery of molecular glues for desired targets is a major challenge and most known molecular glues have been discovered by serendipity. Here we present the first fully synthetic FKBP12-mTOR molecular glues, which were discovered from a FKBP-focused, target-unbiased ligand library. Our biochemical screening of >1000 in-house FKBP ligands yielded one hit that induced dimerization of FKBP12 and the FRB domain of mTOR. The crystal structure of the ternary complex revealed that the hit targeted a similar surface on FRB domain compared to natural product rapamycin but with a radically different interaction pattern. Structure-guided optimization improved potency 500-fold and led to compounds, which initiate FKBP12-FRB complex formation in cells. Our results show that molecular glues targeting flat surfaces can be discovered by focused screening and support the use of FKBP12 as a versatile presenter protein for molecular glues.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"9 1","pages":""},"PeriodicalIF":7.6000,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Science","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4sc06917j","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Molecular glues are a new drug modality with the potential to engage otherwise undruggable targets. However, the rational discovery of molecular glues for desired targets is a major challenge and most known molecular glues have been discovered by serendipity. Here we present the first fully synthetic FKBP12-mTOR molecular glues, which were discovered from a FKBP-focused, target-unbiased ligand library. Our biochemical screening of >1000 in-house FKBP ligands yielded one hit that induced dimerization of FKBP12 and the FRB domain of mTOR. The crystal structure of the ternary complex revealed that the hit targeted a similar surface on FRB domain compared to natural product rapamycin but with a radically different interaction pattern. Structure-guided optimization improved potency 500-fold and led to compounds, which initiate FKBP12-FRB complex formation in cells. Our results show that molecular glues targeting flat surfaces can be discovered by focused screening and support the use of FKBP12 as a versatile presenter protein for molecular glues.
期刊介绍:
Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.