XL01126

• CAT Number: I042838
• CAS Number: 3011029-58-3
• Molecular Formula: C50H64ClFN10O6S2
• Molecular Weight: 1019.69
• Purity: ≥95%
• Synonyms: (2S,4R)-1-[(2R)-3-[[4-[[4-[4-[[5-chloro-4-(methylamino)pyrimidin-2-yl]amino]-3-methoxybenzoyl]piperazin-1-yl]methyl]cyclohexyl]methylsulfanyl]-2-[(1-fluorocyclopropanecarbonyl)amino]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide
• InChI: InChI=1S/C50H64ClFN10O6S2/c1-30-41(69-29-56-30)34-12-10-31(11-13-34)24-54-44(64)39-23-36(63)27-62(39)46(66)42(58-47(67)50(52)16-17-50)49(2,3)70-28-33-8-6-32(7-9-33)26-60-18-20-61(21-19-60)45(65)35-14-15-38(40(22-35)68-5)57-48-55-25-37(51)43(53-4)59-48/h10-15,22,25,29,32-33,36,39,42,63H,6-9,16-21,23-24,26-28H2,1-5H3,(H,54,64)(H,58,67)(H2,53,55,57,59)/t32?,33?,36-,39+,42-/m1/s1
• InChIKey: HKSBXNVKPFTBIG-WUEKOBJSSA-N
• SMILES: CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)C3CC(CN3C(=O)C(C(C)(C)SCC4CCC(CC4)CN5CCN(CC5)C(=O)C6=CC(=C(C=C6)NC7=NC=C(C(=N7)NC)Cl)OC)NC(=O)C8(CC8)F)O

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].
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
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

Reference

[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.
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