Leucine Rich Repeat Kinase 2 (LRRK2) is a member of the leucine-rich repeat kinase family. Researchers found that the mutations in LRRK2 account for approximately 3-4% of Parkinson’s disease patients. LRRK2 mutant expression can induce apoptotic cell death in neuroblastoma cells and in mouse cortical neurons. Similarly, the expression of LRRK2 mutants in vivo causes shortening and simplification of the dendritic cell. Therefore, LRRK2 has become one of the most promising targets for Parkinson’s disease. Besides, LRRK2 is also related to an inflammation of the terminal ileum Crohn’s disease.

In this essay, we will introduce a potent and fast LRRK2 degrader XL01126.

XL01126 degrades LRRK2 by forming a positively cooperative ternary complex with E3 ubiquitin ligase ligand VHL and target protein LRRK2. The LRRK2 degrader exhibits strong degradation performance with DC50s of 14 nM and 32 nM against G2019S LRRK2 and wild-type (WT) LRRK2, respectively, within only 4 hours. XL01126 (300 nM) shows a time-dependent manner in LRRK2 dephosphorylation and pRab10 dephosphorylation as well, with t1/2s of 1.2 h and 0.7 h for WT LRRK2 and WT pRab10, respectively. XL01126 can also induce PDE6D degradation which is LRRK2-independent.

Moreover, it possesses high cell permeability, as shown by the DC50s of 15 nM, 55 nM, and 72 nM of LRRK2 degradation in R1441C LRRK2 mutant MEFs (mouse embryonic fibroblasts), BMDMs (bone marrow-derived macrophages) and PBMCs (peripheral blood mononuclear cells), respectively. Furthermore, this compound performs orally bioavailable and blood-brain barrier (BBB) penetrant in mice. Thus, XL01126 is worthy to be studied for treating Parkinson’s disease.

In conclusion, XL01126 is a strong and fast LRKK2 degrader, with orally bioavailable and BBB penetrant. It can be used to research Parkinson’s disease.


[1] Liu X, et al. J Am Chem Soc. 2022 Aug 25.

[2] Diehl CJ, et al. Chem Soc Rev. 2022 Aug 19.