XL01126 is a potent LRRK2 PROTAC (DC50: 14 nM (G2019S LRRK2) and 32 nM (WT LRRK2)) composed of the VHL ligand VH 101, thiol and the LRRK2 inhibitor HG-10-102-01 . XL01126 crosses the blood-brain barrier and is used as a degradation probe in Parkinson's disease research. XL01126 can be used to study the non-catalytic and framework functions of LRRK2.
XL01126 (300 nM; 4 h) exhibits strong degradation performance by forming a positively cooperative ternary complex with E3 ubiquitin ligase ligand VHL and target protein LRRK2[1].XL01126 (10, 30, 100 nM; 24 h) increases mitophagy in immortalized mouse embryonic fibroblasts cells[1].XL01126 (10 μM; 90 min) displays high permeability in Caco-2 cells[1].XL01126 (10 μM; 0-60 min; every 15 min interval gradient) exhibits high stability in mouse plasma, liver microsome and hepatocyte[1].Pharmacokinetic of XL01126 in vitro[1]
XL01126 (30 mg/kg; p.o.; single dose) shows oral activity with bioavailable value (F) of 15% and can penetrate the blood brain barrier after either oral or parenteral dosing in mice[1].Pharmacokinetic property of XL01126 in mice[1]
References:
[1]. Liu, Xingui, et al. Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bi- oavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2). 2022.