Discovery of fully synthetic FKBP12-mTOR molecular glues.

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

SUBMITTER: Deutscher RCE 

PROVIDER: S-EPMC11796051 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature