Discovery of fully synthetic FKBP12-mTOR molecular glues

26 July 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Molecular glues are a class of drug modalities 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 therefore been discovered by serendipity. Here we present the first fully synthetic FKBP12-mTOR molecular glues, which were dis-covered 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 the binding mode of this hit, which bound to the same surface area as rapamycin, but with a radically dif-ferent interaction pattern. Structure-guided optimization improved potency 500-fold and led to compounds, which initiate FKBP12-FRB complex formation and S6 kinase inhibition in cells. Our results show that molecular glues targeting flat surfac-es can be discovered by focused screening and support the use of FKBP12 as a versatile accessory protein for molecular glues.


Molecular Glue
ternary complex
proximity-based pharmacology

Supplementary materials

Supporting Information
Snythethic protocols, Supplementary Figs, Original data, Characterization of compounds


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