LRRK2-IN-1 Chemical Properties

Boiling point:

787.8±70.0 °C(Predicted)

Density 

1.278

storage temp. 

Store at -20°C

solubility 

≥28.55 mg/mL in DMSO; insoluble in H2O; ≥57.2 mg/mL in EtOH

form 

solid

pka

8.14±0.42(Predicted)

color 

Light yellow to yellow

LRRK2-IN-1 Usage And Synthesis

Description

Leucine-rich repeat kinase 2 (LRRK2) is an enzyme that interacts with parkin, a ligase that is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Loss of function of the parkin protein leads to dopaminergic cell death. The development of Parkinson''s disease has been strongly associated with mutations in the LRRK2 gene that lead to increased kinase activity. LRRK2-IN-1 is a potent inhibitor of LRRK2 that inhibits both wild-type and G2019S mutant LRRK2 (IC₅₀s = 13 and 6 nM, respectively). It is selective for LRRK2 over a large panel of other kinases. LRRK2-IN-1 treatment causes dephosphorylation of LRRK2, leading to its dissociation from 14-3-3 proteins, ubiquitination, and degradation. Inhibitors of LRRK2, including LRRK2-IN-1, stimulate macroautophagy in H4 neuroglioma cells.

Uses

LRRK2-IN-1 is a benzodiazepine based derivative and is known as a selective inhibitor of the Parkinson''s disease kinase LRRK2.

Definition

ChEBI: LRRK2-IN-1 is a member of the class of pyrimidobenzodiazepines that is 5,11-dimethylpyrimido[4,5-b][1,4]benzodiazepin-6-one carrying at C-2 on the pyrimidine ring a 4-[(4-methylpiperazin-1-yl)piperidine-1-carbonyl]-2-methoxyanilino substituent. It is an inhibitor of the Parkinson's disease kinase LRRK2. It has a role as an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor and an antineoplastic agent. It is a N-acylpiperidine, a N-alkylpiperazine, an aromatic ether, a pyrimidobenzodiazepine, an aromatic amine, a secondary amino compound and a tertiary amino compound.

in vivo

storage

Store at -20°C

References

[1] XIANMING DENG. Characterization of a selective inhibitor of the Parkinson”s disease kinase LRRK2[J]. Nature chemical biology, 2011, 7 4: 203-205. DOI: 10.1038/nchembio.538
[2] JING ZHAO. LRRK2 dephosphorylation increases its ubiquitination.[J]. Biochemical Journal, 2015, 469 1: 107-120. DOI: 10.1042/bj20141305
[3] CLAUDIA MANZONI . Inhibition of LRRK2 kinase activity stimulates macroautophagy[J]. Biochimica et biophysica acta. Molecular cell research, 2013, 1833 12: Pages 2900-2910. DOI: 10.1016/j.bbamcr.2013.07.020
[4] ALAVI M V. Tau phosphorylation and OPA1 proteolysis are unrelated events: Implications for Alzheimer’s Disease[J]. Biochimica et biophysica acta. Molecular cell research, 2021, 1868 12: Article 119116. DOI: 10.1016/j.bbamcr.2021.119116

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