JH-XII-03-02   Click here for help

GtoPdb Ligand ID: 12908

Synonyms: compound 6 [PMID: 37591317]
Compound class: Synthetic organic
Comment: JH-XII-03-02 is a LRRK2 PROTAC degrader molecule [1]. It simultaneously inhibits LRRK2 kinase activity and disrupts LRRK2's scaffolding function. Reducing LRRK2 activity is being investigated for potential to treat Parkinson's disease that is caused by inherited LRRK2 mutations. JH-XII-03-02 promotes cereblon-mediated degradation of LRRK2.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 19
Hydrogen bond donors 3
Rotatable bonds 22
Topological polar surface area 214.39
Molecular weight 853.92
XLogP -0.8
No. Lipinski's rules broken 3
SMILES / InChI / InChIKey
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Canonical SMILES CC1(CC1)OC2=CC3=C(C=C2)NN=C3C4=NC=NC(=C4)N5CCN(CC5)C(=O)CCOCCOCCOCCOCCNC6=C7C(=CC=C6)C(=O)N(C8CCC(=O)NC8=O)C7=O
Isomeric SMILES CC1(CC1)OC2=CC=C3C(=C2)C(=NN3)C4=NC=NC(=C4)N5CCN(CC5)C(=O)CCOCCOCCOCCOCCNC6=C7C(=CC=C6)C(=O)N(C8CCC(=O)NC8=O)C7=O
InChI InChI=1S/C43H51N9O10/c1-43(10-11-43)62-28-5-6-31-30(25-28)39(49-48-31)33-26-35(46-27-45-33)50-13-15-51(16-14-50)37(54)9-17-58-19-21-60-23-24-61-22-20-59-18-12-44-32-4-2-3-29-38(32)42(57)52(41(29)56)34-7-8-36(53)47-40(34)55/h2-6,25-27,34,44H,7-24H2,1H3,(H,48,49)(H,47,53,55)
InChI Key XYGRYBJBOSXMHE-UHFFFAOYSA-N
Bioactivity Comments
JH-XII-03-02 retains LRRK2 inhibition potency for wild type LRRK2 and LRRK2G2019S, and it is highly selective for LRRK2 in a KINOMEscan [1]. In a cell-based assay 1μM JH-XII-03-02 almost completely degrades LRRK2 protein after 48 hours incubation.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
leucine rich repeat kinase 2 Hs Inhibitor Inhibition 9.0 pIC50 - 1
pIC50 9.0 (IC50 1x10-9 M) [1]
Description: Inhibition of WT LRRK2 activity