XL01126   Click here for help

GtoPdb Ligand ID: 12009

Compound class: Synthetic organic
Comment: XL01126 is a VHL-based PROTAC degrader targeting leucine rich repeat kinase 2 (LRRK2). The LRRK2 binding moeity of the compound is the brain-penetrant kinase inhibitor HG-10-102-01. XL01126 is orally bioavailable and retains the ability of the parent kinase inhibitor to cross the blood-brain barrier. LRRK2 is an active therapeutic target for Parkinson's disease, since activating coding mutations in LRRK2 are associated with dominantly inherited Parkinson's disease [1-2,5]. XL01126's development was led by Dundee University's Centre for Targeted Protein Degradation and the Research Institute for Medicines at the University of Lisbon. Initially disclosed in a ChemRxiv preprint [4].

Cereblon-targeting LRRK2 PROTACs have been disclosed previously, but these were found to be inefficient target degraders [3].
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 15
Hydrogen bond donors 5
Rotatable bonds 22
Topological polar surface area 247.79
Molecular weight 998.47
XLogP 5.05
No. Lipinski's rules broken 3
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Canonical SMILES COc1cc(ccc1Nc1ncc(c(n1)NC)C)C(=O)N1CCN(CC1)C[C@@H]1CC[C@H](CC1)CSC([C@@H](C(=O)N1C[C@@H](C[C@H]1C(=O)NCc1ccc(cc1)c1scnc1C)O)NC(=O)C1(F)CC1)(C)C
Isomeric SMILES CNc1nc(Nc2ccc(cc2OC)C(=O)N2CCN(C[C@H]3CC[C@H](CSC(C)(C)[C@H](NC(=O)C4(F)CC4)C(=O)N4C[C@H](O)C[C@H]4C(=O)NCc4ccc(cc4)c4scnc4C)CC3)CC2)ncc1C
InChI InChI=1S/C51H67FN10O6S2/c1-31-25-55-49(59-44(31)53-5)57-39-16-15-37(23-41(39)68-6)46(65)61-21-19-60(20-22-61)27-34-7-9-35(10-8-34)29-70-50(3,4)43(58-48(67)51(52)17-18-51)47(66)62-28-38(63)24-40(62)45(64)54-26-33-11-13-36(14-12-33)42-32(2)56-30-69-42/h11-16,23,25,30,34-35,38,40,43,63H,7-10,17-22,24,26-29H2,1-6H3,(H,54,64)(H,58,67)(H2,53,55,57,59)/t34-,35-,38-,40+,43-/m1/s1
1. Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I, Matyszewski M, Donosa O, Watanabe R, Böhning J, Shiau AK et al.. (2020)
Structure of LRRK2 in Parkinson's disease and model for microtubule interaction.
Nature, 588 (7837): 344-349. [PMID:32814344]
2. Erb ML, Moore DJ. (2020)
LRRK2 and the Endolysosomal System in Parkinson's Disease.
J Parkinsons Dis, 10 (4): 1271-1291. [PMID:33044192]
3. Konstantinidou M, Oun A, Pathak P, Zhang B, Wang Z, Ter Brake F, Dolga AM, Kortholt A, Dömling A. (2021)
The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2).
ChemMedChem, 16 (6): 959-965. [PMID:33278061]
4. Liu X, Kalogeropulou K, Domingos S, Makukhin N, Nirujogi R, Singh F, Shpiro N, Saalfrank A, Sammler E, Ganley I et al.. (2022)
Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Oral bioavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2).
chemrxiv, Preprint. DOI: 10.26434/chemrxiv-2022-4gzm0
5. Rideout H, Greggio E, Kortholt A, Nichols RJ. (2022)
Editorial: LRRK2-Fifteen Years From Cloning to the Clinic.
Front Neurosci, 16: 880914. [PMID:35478845]