XL01126

XL01126 is a potent degrader of LRRK2 with DC₅₀s of 14 nM (G2019S LRRK2) and 32 nM (WT LRRK2), respectively. XL01126 can cross blood-brain barrier and be used as a degrader probe in Parkinson’s disease research. XL01126 exerts function of study of non-catalytic and scaffolding functions of LRRK2^[1]. IC50 & Target:DC50: 15-72 nM (LRRK2)^[1] In Vitro: 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]

Parameter	Properties
T1/2 in mouse plasma	108.29 min
T1/2 in mouse liver microsome	3.65 min
Clint in mouse liver microsome	1494.62 mL/min/kg
T1/2 in mose hepatocytes	314.33 min
Clint in mose hepatocytes	26.04 mL/min/kg

In Vivo: 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]

Route	Dose (mg/kg)	CL (L/h/kg)	Vss (L/kg)	Tmax (h)	Cmax (ng/mL)	T1/2 (h)	AUClast (h·ng/mL)	AUCinf (h·ng/mL)	MRT (h)	F (%)
p.o.	30			2	3620	21.9	21337	109271		15
i.v.	5	0.208	0.511			1.52	23663	23981	2.45
i.p.	30			0.25	7700	5.2	41434	64068		29.2