LRRK2 Inhibitors

Leucine-rich repeat kinase 2 (LRRK2) is a protein localized in both the cytoplasm and the outer membrane of mitochondria. Gain-of-function mutations in LRRK2 have been linked to an elevated risk of Crohn’s disease as well as Parkinson’s disease. Parkinson’s disease models indicate that such mutations can disrupt vesicular transport, autophagy, protein synthesis, and cytoskeletal organization.

LRRK2 is known to interact with Parkin, an E3 ubiquitin ligase critical for protein degradation. Mutations in Parkin are associated with a juvenile familial form of Parkinson’s disease. Experimental expression of mutant LRRK2 in cultured neurons leads to dendritic shortening. Other variants can trigger calcium dysregulation, promote autophagic removal of mitochondria, and drive neurodegeneration and inflammation—hallmarks of Parkinson’s pathology.

At present, therapeutic strategies to halt or slow the progression of Parkinson’s disease remain limited. While certain experimental agents have demonstrated activity in research models, the field is still emerging. Notably, inhibition of LRRK2 reduces its kinase activity and has been shown to mitigate Parkinson’s-related abnormalities in both cellular and animal systems.

Aladdin Scientific offers several LRRK2 inhibitors under investigation for their neuroprotective potential:

· PF-06447475 (P413944 ≥99% Super high purity,  P421809 10mM in DMSO) – Reduces neurodegeneration and inflammation induced by α-synuclein in animal models.

· CZC-54252 (C413507 ≥98% high purity, C420851 10mM in DMSO) – In vitro, protects rodent and human neurons from damage caused by mutant LRRK2.

· GNE-7915 (G275946 ≥98% high purity, G421335 10mM in DMSO) – Potently inhibits LRRK2 activity across multiple species.

References

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2. Smith WW, Pei Z, Jiang H, Moore DJ, et al. Proc Natl Acad Sci U S A. 2005;102(51):18676-81.

3. MacLeod D, Dowman J, Hammond R, et al. Neuron. 2006;52(4):587-93.

4. Cherra SJ 3rd, Steer E, Gusdon AM, et al. Am J Pathol. 2013;182(2):474-84.

5. Ramsden N, Perrin J, Ren Z, et al. ACS Chem Biol. 2011;6(10):1021-8.

6. Estrada AA, Liu X, Baker-Glenn C, et al. J Med Chem. 2012;55(22):9416-33.

Aladdin: https://www.aladdinsci.com/