LRRK2:14-3-3 molecular glue compounds

LRRK2:14-3-3 molecular glue compounds are a novel class of small-molecule protein-protein interaction (PPI) stabilizers designed for the treatment of Parkinson's disease. Leucine-Rich Repeat Kinase 2 (LRRK2) is a major genetic risk factor and therapeutic target in Parkinson's disease, where mutations such as G2019S lead to kinase hyperactivity and neurotoxicity. Under physiological conditions, LRRK2 forms an inactive complex with 14-3-3 scaffold proteins, which requires phosphorylation of LRRK2 at S910 and S935. This protective interaction is weakened in PD-associated LRRK2 mutants. These molecular glues stabilize the LRRK2:14-3-3 complex, promoting LRRK2 S935 phosphorylation and reducing downstream pathological markers of LRRK2 activity, such as pT73-Rab10, thereby offering a novel allosteric strategy to mitigate LRRK2-mediated neurodegeneration.

Other names

14-3-3:LRRK2 stabilizersLRRK2:14-3-3 stabilizersmolecular glues of the LRRK2:14-3-3 complexmolecular glues of the LRRK2:14-3-3 interaction