Discovery of fully synthetic FKBP12-mTOR molecular glues
Robin C. E. Deutscher, Christian Meyners, Maximilian Repity, Wisely Oki Sugiarto, Jürgen Kolos, Edvaldo Vasconcelos Soares Maciel, Tim Heymann, Thomas Geiger, Stefan Knapp, Frederik Lermyte, Felix Hausch
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 the 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.