MLi-2 / Merck (MSD) - LARVOL DELTA

Striatal cell-type-specific molecular signatures reveal potential therapeutic targets in a model of dystonia. (PubMed, Neurobiol Dis) - "The pattern of mRNA dysregulation was distinct from parkinsonism where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. By leveraging these disease-specific molecular signatures, we identified LRRK2 inhibition, among other mechanisms, as a novel therapeutic target for dystonia."

Journal • CNS Disorders • Dystonia • Movement Disorders • Parkinson's Disease • LRRK2

MILD HYPEREMIA IN THE ABSENCE OF BOWEL WALL THICKENING ON INTESTINAL ULTRASOUND IS ASSOCIATED WITH BIOCHEMICAL DISEASE ACTIVITY AND WORSE DISEASE OUTCOMES IN PATIENTS WITH CROHN'S DISEASE AND ULCERATIVE COLITIS (DDW 2025) - "We excluded pts with mLim2 or 3, BWT >3mm anywhere on index IUS, or mLim1 at surgical anastomoses only...Although PDO in UC was numerically higher in mLim1, this was not statistically significant likely due to small cohort size. These findings support the consideration of treatment adjustments when this isolated parameter is identified and inform future IUS treat-to-target strategies."

Clinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • CRP

Expanding Therapeutic Horizons with Indazole-Based Compounds: A Review of Anticancer, Antimicrobial, and Neuroprotective Applications. (PubMed, Med Chem) - "Additionally, the LRRK2 antagonist MLi-2 demonstrated remarkable efficacy in treating neurodegenerative diseases, while indazole-5-carboxamides exhibited a strong affinity for monoamine oxidases, potentially offering new therapeutic options for Parkinson's disease. Inhibition of COX-2 and FGFR resulted in anti-inflammatory effects, with minimal off-target damage observed in vivo. Collectively, our findings underscore the therapeutic versatility of indazole frameworks across various disease pathways, suggesting their potential for developing innovative treatments for cancer, infections, metabolic disorders, and neurological conditions."

Journal • Breast Cancer • CNS Disorders • Genetic Disorders • Hepatocellular Cancer • Hepatology • HER2 Breast Cancer • HER2 Positive Breast Cancer • Infectious Disease • Metabolic Disorders • Movement Disorders • Obesity • Oncology • Parkinson's Disease • Solid Tumor • CDC37 • CDK2 • EGFR • HER-2 • HSP90AA1 • KDR • LRRK2 • MET

ACUTE KNOCKDOWN OF LRRK2 INCREASES SYNAPTIC-VESICLE SIZE AND AUGMENTS EXOCYTOSIS. ** WITHDRAWN BY AUTHOR** (ADPD 2025) - "These effects are unlikely to be due to inhibition of Lrrk2 kinase activity, because treating neurons with a highly selective kinase inhibitor (MLi-2) did not result in similar phenotypes... Our data advocate a structural, non-enzymatic role of Lrrk2 in modulating membranes at synapses and provide new insights into its physiologic role. Specific domaisn leading to these phenotypes are currently being investigated."

CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Effect of LRRK2 Inhibition on the Activity of Glucocerebrosidase in Patient-Specific Cells from Patients with Gaucher Disease. (PubMed, Biochemistry (Mosc)) - "The activity of GCase and the levels of its substrate in cells cultured with and without MLi-2 was assayed by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). No effect of LRRK2 inhibition on the activity GCase in a group of patients with GD was found."

Journal • CNS Disorders • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • GBA1 • LRRK2

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson's disease. (PubMed, Brain) - "Freshly collected PBMCs from 3 G2019S L2PD, 1 R1441G L2PD, 1 iPD, and 5 controls (n=10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in-vitro administration of the MLi-2 LRRK2 inhibitor...Our data suggest that monitoring pSer106 RAB12 phosphorylation could be a relevant biomarker for tracking LRRK2 activation, particularly in G2019S carriers. Future work may determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials."

Biomarker • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LAMP1 • LRRK2

The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2). (PubMed, J Neurochem) - "The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment...This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • LRRK2 • SLC1A2

LRRK2 and RAB8A regulate cell death after lysosomal damage in macrophages through cholesterol-related pathways. (PubMed, Neurobiol Dis) - "U18666A-treated cells were less sensitive to LLOMe-induced cell death, but the attenuation of cell death by LRRK2 inhibition was strongly reduced suggesting that LRRK2 inhibition and lysosomal cholesterol reduces cell death by overlapping mechanisms. Thus, our data demonstrates a LRRK2- and RAB8A-mediated attenuation of RAW 264.7 cell death induced by lysosomal damage that is modulated by lysosomal cholesterol."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Metagenomic Insights into Coal Slag Remediation Effects on Soil and Microbial Health in Qinghai's Muli Coal Mine. (PubMed, Microorganisms) - "From the perspective of overall ecological restoration, this study concluded that the MLII2 treatment group exhibited the most favorable ecological restoration outcomes. This finding emphasizes the importance of not only enhancing microbial diversity but also prioritizing the restoration of community functions, especially for the recovery of fragile high-altitude ecosystems."

Journal

Mild Hyperemia in the Absence of Bowel Wall Thickening on Intestinal Ultrasound is Associated With Clinical and Biochemical Disease Activity and Worse Disease Outcomes in Patients With Crohn's Disease (ACG 2024) - "We excluded pts with mLim2 or 3, BWT >3mm anywhere on index IUS or those with mLim1 at surgical anastomoses only... We identified 33 pts (15 with mLim1, 18 with mLim0 (Table 1)). 8 (53.3%) pts with mLim1 and 7 (38.9%) with mLim0 had at least one marker of active disease at the time of index IUS. Of the 7 mLim1 pts in clinical remission at index IUS, 5 (71.4%) had a poor disease outcome within 1 year with median time to a poor disease outcome of 103 days (IQR 39.5-154)."

Clinical • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease • CRP

Striatal cell-type-specific molecular signatures reveal therapeutic targets in a model of dystonia. (PubMed, bioRxiv) - "We leveraged the unique molecular signatures of dSPNs and iSPNs in DRD mice to identify biochemical mechanisms that may be targets for therapeutics, including LRRK2 inhibition. Administration of the LRRK2 inhibitor MLi-2 ameliorated the dystonia in DRD mice suggesting a novel target for therapeutics and demonstrating that the delineation of cell-type-specific molecular signatures provides a powerful approach to revealing both CNS dysfunction and therapeutic targets in dystonia."

Journal • CNS Disorders • Dystonia • Movement Disorders • Parkinson's Disease • LRRK2

Lrrk2-mediated endolysosomal dysregulation in pff-induced neuronal senescence (Neuroscience 2024) - "Intervention with the specific LRRK2 kinase inhibitor, MLi-2, effectively reversed the increase in lysosomal enzyme levels and restored chromatin structure, as demonstrated by ATAC-seq analysis. Our findings underscore a critical role for LRRK2 in PFF-induced endolysosomal dysregulation and neuronal senescence, enhancing our understanding of the molecular pathways and offering new therapeutic avenues targeting LRRK2 and Rab5 activities."

CNS Disorders • LMNB1 • LRRK2 • RAB5A

Kit Ligand Acutely Modulates the Inhibition of Purkinje Cells (Neuroscience 2024) - "MLI types include MLI-1, which directly inhibit PCs, and MLI-2 which inhibit MLI-1s...Revealing the cell and circuit mechanisms of PC inhibition will ultimately inform the basis of cerebellar dependent learning, behavior, and non-motor functions. Furthermore, elucidating the mechanisms of KL-Kit in adult synapse biology may introduce new pathways of synaptic plasticity relevant to the other circuits in which these gene products are expressed."

CNS Disorders • Psychiatry • KIT

Identifying the association between melanoma and Parkinson's (Neuroscience 2024) - "Furthermore, globally inhibiting LRRK2 kinase activity using Merck LRRK2 inhibitor-2 (MLi-2) in rodent diet at a concentration of 55 mg/kg/day reduces melanoma growth, an effect that is even stronger in GS mice...Instead, the impact of LRRK2 kinase on melanoma growth appears to require the tumor microenvironment and may be mediated by sympathetic innervation. Consistent with this idea, co-cultured sympathetic neurons and melanoma cells interact dynamically in vitro.Investigating the impact of LRRK2-G2019S on the melanoma microenvironment will define key events in melanoma progression and reveal how changes in cellular dynamics drive shared risk between melanoma and Parkinson’s."

CNS Disorders • Parkinson's Disease • LRRK2

Decoding Inhibitor Egression from Wild-Type and G2019S Mutant LRRK2 Kinase: Insights into Unbinding Mechanisms for Precision Drug Design in Parkinson's Disease. (PubMed, J Phys Chem B) - "Here, two ATP-competitive type I inhibitors, PF-06447475 and MLi-2 (Comp1 and Comp2 ), and one non-ATP-competitive type II inhibitor, rebastinib (Comp3), were considered for this investigation. The binding energy and residence time of the inhibitors followed a similar trend to experimental observations. The findings of this work might provide insight into designing more potent inhibitors for the G2019S LRRK2 kinase."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • CHEK1 • LRRK2

LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants. (PubMed, Neurobiol Dis) - "We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria."

Journal • CNS Disorders • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Specialized connectivity of molecular layer interneuron subtypes leads to disinhibition and synchronous inhibition of cerebellar Purkinje cells. (PubMed, Neuron) - "Here, we find that two recently recognized MLI subtypes, MLI1 and MLI2, have a highly specialized connectivity that allows them to serve distinct functional roles...MLI2s are not electrically coupled, primarily inhibit MLI1s and disinhibit PCs, and are well suited to gating cerebellar-dependent behavior and learning. The synchronous firing of electrically coupled MLI1s and disinhibition provided by MLI2s require a major re-evaluation of cerebellar processing."

Journal

Pharmacological Inhibition of LRRK2 Exhibits Neuroprotective Activity in Mouse Photothrombotic Stroke Model. (PubMed, Exp Neurobiol) - "Interestingly, stroke infarct volumes were significantly reduced, and neurological deficits were diminished by pharmacological inhibition of LRRK2 kinase activity using MLi-2, a brain-penetrant LRRK2 kinase inhibitor...These results suggest that pharmacological inhibition of LRRK2 kinase activity could attenuate mitochondrial apoptosis, ultimately leading to neuroprotective potential in stroke progression. In conclusion, LRRK2 kinase activity might be neuro-pathogenic due to impaired mitophagy in stroke progression, and pharmacological inhibition of LRRK2 kinase activity could be beneficial in reducing the risk of stroke in patients with LRRK2 mutations."

Journal • Preclinical • Cardiovascular • CNS Disorders • Hematological Disorders • Ischemic stroke • Movement Disorders • Parkinson's Disease • Thrombosis • LRRK2

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression. (PubMed, Transl Neurodegener) - "This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

METABOLIC ALTERATIONS IN LRRK2 G2019S MICROGLIA DERIVING FROM STEM CELLS OF PD PATIENTS (ADPD 2024) - "With microglia being the immune cells of the brain, we hope that this study will provide invaluable insights into their role in PD and shed more light in the underlying mechanisms of LRRK2-PD penetrance."

Clinical • IFNG • LRRK2

INVESTIGATING THE INTERACTIONS BETWEEN LRRK2 AND GBA1 IN MOUSE AND HUMAN IPSC-DERIVED ASTROCYTES IN PARKINSON DISEASE (ADPD 2024) - " Mouse and hiPSC-derived astrocytes carrying the G2019S-LRRK2 and/or N370S-GBA1 mutations were treated with the LRRK2 kinase inhibitor MLi-2 for 24 hours or the lysomotropic drug chloroquine for 5 hours, which has been shown to enhance LRRK2-dependent phosphorylation of Rab8A/10. Understanding the mechanisms of which GBA and LRRK2 interact within the lysosomal pathway will increase our knowledge of how the two genes cause disease as well as help identify possible drug targets for GBA1- or LRRK2- associated Parkinson disease."

Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • GBA • LRRK2 • RAB10

UNDERSTANDING THE CONSEQUENCE OF LRRK2 DYSREGULATION IN HUMAN STEM CELL DERIVED ASTROCYTES (ADPD 2024) - "Thus, ongoing work aims to establish whether the LRRK2R1441C/R1441C pathogenic phenotype can be reversed following LRRK2 kinase inhibition (MLi2) or LRRK2 protein degradation (XL01126)... Overall, the results show that astrocytes with LRRK2 mutations exhibit alterations in mitochondrial bioenergetics and inflammatory profile. Future work aims to utilise unbiased proteomics and mitochondrial proteomics to establish the pathways underpinning these phenotypes, allowing for the identification of therapeutic targets."

CNS Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation • LRRK2

THE IMPACT OF LRRK2 KINASE INHIBITION ON GUT-TO-BRAIN SPREADING IN NOVEL PD MOUSE MODELS (ADPD 2024) - "The MLi-2 treatment performed in the novel PD transgenic mice described above, will be valuable to assess whether the inhibition of the LRRK2 impacts periphery-to-brain transfer of a-syn. The results from this study will help shed light on whether LRRK2 inhibition could be a therapeutic target capable of slowing down PD progression."

Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Differential LRRK2 Signalling and Gene Expression in WT-LRRK2 and G2019S-LRRK2 Mouse Microglia Treated with Zymosan and MLi2. (PubMed, Cells) - "Overall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CTSB • GPNMB • LRRK2 • TLR2 • TLR4

Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice. (PubMed, NPJ Parkinsons Dis) - "As a corollary, VKI animals show a significant increase in amphetamine induced hyperlocomotion, compared to Haplo mice, that is also abolished by MLi-2. Taken together, these data show Vps35 p.D620N confers a gain-of-function with respect to LRRK2 kinase activity, and that VPS35 and LRRK2 functionally interact to regulate DAT function and striatal dopamine transmission."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2 • RAB10