TY  - JOUR
AU  - Deutscher, Robin C E
AU  - Meyners, Christian
AU  - Repity, Maximilian L
AU  - Sugiarto, Wisely Oki
AU  - Kolos, Jürgen M
AU  - Maciel, Edvaldo V S
AU  - Heymann, Tim
AU  - Geiger, Thomas M
AU  - Knapp, Stefan
AU  - Lermyte, Frederik
AU  - Hausch, Felix
TI  - Discovery of fully synthetic FKBP12-mTOR molecular glues.
JO  - Chemical science
VL  - 16
IS  - 10
SN  - 2041-6520
CY  - Cambridge
PB  - RSC
M1  - DKFZ-2025-00319
SP  - 4256-4263
PY  - 2025
N1  - 2025 Jan 13;16(10):4256-4263
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:39916884
C2  - pmc:PMC11796051
DO  - DOI:10.1039/D4SC06917J
UR  - https://inrepo02.dkfz.de/record/298619
ER  -