FK506-binding protein 12-recruited proteins (FKBP12-recruited targets)

Disease-relevant proteins recruited via FKBP12 refers to a class of therapeutic targets modulated through an induced proximity mechanism involving the immunophilin FK506-binding protein 12 (FKBP12). In this approach, a small molecule acts as a 'molecular glue' or 'tri-complex' inducer, binding simultaneously to FKBP12 and a target protein to form a stable ternary complex. This strategy was first identified with natural products like rapamycin and FK506, which recruit mTOR and calcineurin, respectively, to mediate immunosuppression (Schreiber, 1991). More recently, this platform has been adapted to target previously 'undruggable' oncogenic proteins, most notably the active (GTP-bound) forms of the RAS GTPase family, including KRAS, NRAS, and HRAS (Nichols et al., 2022). By utilizing the high cellular abundance of FKBP12, these inhibitors can sterically block the interaction between the target protein and its downstream effectors with high specificity for particular mutant conformations. This modality represents a significant advancement in precision medicine, offering a way to target specific protein states and mutations that are inaccessible to traditional small-molecule inhibitors.

Other names

FKBP12-recruited targetsTri-complex targetsFKBP12-dependent neo-substratesRAS(ON) targetsFKBP12-mediated induced proximity targets

Induced proximity via tri-complex formation where FKBP12 acts as a co-receptor to sterically hinder the target protein's active site or its interaction with downstream effectors.