PF-06447475 / Pfizer - LARVOL DELTA

REBALANCE OF MITOPHAGY BY INHIBITING LRRK2 IMPROVES COLON ALTERATIONS IN AN MPTP IN VIVO MODEL (ADPD 2025) - "We aimed to evaluate whether the selective inhibitor of LRRK2, PF -06447475 (PF -475), attenuates the PD in central nervous system (CNS) and in the gastrointestinal system... Results suggested that LRRK2 inhibition by PF -475 may attenuate gastrointestinal dysfunction associated to PD."

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

Rebalance of mitophagy by inhibiting LRRK2 improves colon alterations in an MPTP in vivo model. (PubMed, iScience) - "We aimed to evaluate whether the selective inhibitor of LRRK2, PF-06447475 (PF-475), attenuates the PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in central nervous system (CNS) and in the gastrointestinal system...LRRK2 inhibition suppressed MPTP-induced enteric dopaminergic neuronal injury and protected tight junction in the colon. Results suggested that PF-475 may attenuate gastrointestinal dysfunction associated to PD."

Journal • Preclinical • CNS Disorders • Gastrointestinal Disorder • Movement Disorders • Parkinson's Disease • LRRK2

Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD). (PubMed, Neurotox Res) - "Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Movement Disorders • Parkinson's Disease • CASP3 • 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 Inhibitor PF-06447475 Protects Drosophila melanogaster against Paraquat-Induced Locomotor Impairment, Life Span Reduction, and Oxidative Stress. (PubMed, Neurochem Res) - "Since LRRK2 is an evolutionary conserved kinase, the present findings reinforce the idea that either reduction or inhibition of the LRRK2 kinase might decrease OS and locomotor alterations associated with PD. Our observations highlight the importance of uncovering the function of the hLRRK2 orthologue dLrrk2 in D. melanogaster as an excellent model for pharmacological screenings."

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

LRRK2 regulates ferroptosis through the system Xc-GSH-GPX4 pathway in the neuroinflammatory mechanism of Parkinson's disease. (PubMed, J Cell Physiol) - "LRRK2 and P-P65 expression inhibition with PF-06447475 attenuated microglia activation in the nigrostriatal dense part of MPTP-treated mice. Based on our findings, it is evident that LRRK2 plays a critical role in promoting the neuroinflammatory response during the pathogenesis of PD by regulating the system Xc-GSH-GPX4 pathway. Taken together, our data highlights the potential research and therapeutic value of targeting LRRK2 to regulate neuroinflammatory response in PD through ferroptosis."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • GPX4 • LRRK2 • RELA

Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors. (PubMed, J Med Chem) - "The distinct cellular functions of closely related MST kinases can now be elucidated with subfamily-selective chemical tool compounds using a combination of the MST1/2 inhibitor PF-06447475 (2) and the two MST3/4 inhibitors developed. We found that MST3/4-selective inhibition caused a cell-cycle arrest in the G1 phase, whereas MST1/2 inhibition resulted in accumulation of cells in the G2/M phase."

Journal • Oncology

REBALANCE OF MITOPHAGY BY INHIBITING LRRK2 IMPROVES PARKINSON'S DISEASE-RELATED COLON DYSFUNCTIONS (ADPD 2024) - "We aimed to evaluate whether the selective inhibitor of LRRK2, PF-06447475 (PF-475), attenuates the PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in CNS and in the gastrointestinal system... We indicated that selective inhibition of LRRK2 restores disruption of colonic integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model via the mitoautophagy pathway, suggesting that PF-475 may attenuate gastrointestinal dysfunction associated with PD."

CNS Disorders • Gastrointestinal Disorder • Inflammation • Movement Disorders • Parkinson's Disease • LAMP2 • LRRK2 • OCLN • OPTN • TJP1

Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2). (PubMed, J Med Chem) - "In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [C]3 ([C]PF-06447475) and [F]4 ([F]PF-06455943)...More importantly, [F]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers."

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

High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis. (PubMed, Int J Mol Sci) - "Importantly, the inhibitor of the LRRK2 kinase PF-06447475 (PF-475) almost completely blunted ROT-induced apoptosis and reduced ROT-induced accumulation of lysosomes in both acute and chronic conditions in DALNs...Given that defects in mitochondrial complex I activity are commonly observed in PD, ROT works well as a chemical model of PD in both acute and chronic conditions. Therefore, prevention and treatment therapy should be guided to relieve DALNs from mitochondrial damage and OS, two of the most important triggers in the apoptotic cell death of DALNs."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • BDNF • CASP3 • LRRK2 • MAP1B • PRKN

Structural insight into G2019S mutated LRRK2 kinase and brain-penetrant type I inhibitor complex: a molecular dynamics approach. (PubMed, J Biomol Struct Dyn) - "Three reported potent and brain-penetrant inhibitors, GNE-7915, PF-06447475 and MLi-2 (comp1, comp2 and comp3 respectively) and also, another two inhibitors, Pyrrolo[2,3-b] pyridine derivative (comp4) and Pyrrolo[2,3-d] pyrimidine derivative (comp5), were used. Finally, MLi-2 showed a conformational rearrangement by dihedral flipping in both WT and mutated systems but got stability in G2019S LRRK2. This work could potentially help design more improved and effective Type I inhibitors for G2019S LRRK2 kinase."

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

LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner. (PubMed, Cell Death Dis) - "In contrast, treatment with the specific LRRK2 kinase inhibitors MLi-2 (100 nM) or PF-06447475 (150 nM), which also led to decreased LRRK2 phosphorylation of S910/S935/S955/S973, did not affect autophagy. Similarly, reduced autophagy and decreased LRRK2 phosphorylation at the constitutive sites were observed in cells expressing the pathological R1441C LRRK2 PD mutant, which also displays increased kinase activity. These data underscore the relation between LRRK2 phosphorylation at its constitutive sites and the importance of increased LRRK2 kinase activity in autophagy regulation and PD pathology."

Journal • CNS Disorders • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease • Movement Disorders • Oncology • Parkinson's Disease • RAB10

LRRK2 Kinase Inhibition Attenuates Neuroinflammation and Cytotoxicity in Animal Models of Alzheimer's and Parkinson's Disease-Related Neuroinflammation. (PubMed, Cells) - "Specifically, we reported that LRRK2 kinase inhibition with MLi2 and PF-06447475 (PF) molecules attenuated neuroinflammation, gliosis and cytotoxicity in mice with intracerebral injection of Aβ fibrils or α-syn preformed fibrils (pffs). Moreover, for the first time in vivo, we showed that LRRK2 kinase activity participates in AD-related neuroinflammation and therefore might contribute to AD pathogenesis. Overall, our findings added evidence on the anti-inflammatory effects of LRRK2 kinase inhibition in preclinical models and indicate that targeting LRRK2 activity could be a disease-modifying treatment for NDDs with an inflammatory component."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

Inhibition of LRRK2 Attenuates Depression-Related Symptoms in Mice with Moderate Traumatic Brain Injury. (PubMed, Cells) - "The aim of this study was to investigate the role of LRRK2 in reducing depression-related symptoms after mTBI and to determine whether inhibition of LRRK2 mediated by PF-06447475 could have antidepressant effects...Thus, this study has shown that mTBI induction promotes the development of depression-like behavioral changes. LRRK2 inhibition showed an antidepressant effect and restored the changes in the copper/glutamate/N-methyl-D-aspartic acid receptor (Cu/NMDAR) system."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mental Retardation • Psychiatry • Vascular Neurology

Lrrk-2 inhibition by pf06447475 modulates neuronal damage and immunity after spinal cord trauma (Neuroscience 2022) - "Moreover, the accumulation of CD4+ and CD8+ cells throughout the spinal cord lesion site of SCI mice as well CD45+ and CD68+ cells was reduced by PF06447475 administration at the higher dose of 10 mg/kg. Our results suggest that the correlations between LRRK2, neurodegeneration and immunity exist and that LRRK2"

CNS Disorders • Parkinson's Disease • CD68 • CD8 • IFNG • IL10 • IL6 • PTPRC • TNFA

LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma. (PubMed, Antioxidants (Basel)) - "Furthermore, oxidative stress and cytokines expression levels, including interleukins (IL-1, IL-6, IL-10, and 12), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), secreted and released after trauma were decreased by LRRK2 antagonist treatments. Our results suggest that the correlations between LRRK2 and inflammation of the CNS exist and that LRRK2 activity targeting could have direct effects on the intervention of neuroinflammatory disorders."

Journal • CNS Disorders • Immunology • Inflammation • Movement Disorders • Oncology • Orthopedics • Parkinson's Disease • IFNG • IL10 • IL6 • TNFA

LRRK-2 Inhibition By PF06447475 Treatment Reduces Neuronal Damage and Immune Response After Spinal Cord Trauma. (PubMed, FASEB J) - "Moreover, the accumulation of CD4 and CD8 cells throughout the spinal cord lesion site of SCI mice was reduced by PF-06447475 oral administration at the dose of 10 mg/kg. Taken together, our results suggest that exist a mutual correlation between LRRK2, neurodegeneration and immunity and that LRRK2 inhibition could have direct effects on the intervention of neuroinflammatory disorders."

Journal • CNS Disorders • Immunology • Inflammation • Movement Disorders • Oncology • Orthopedics • Parkinson's Disease • CD4 • CD8 • IFNG • IL10 • IL6 • TNFA

Inhibition of LRRK2-Rab10 Pathway Improves Secondary Brain Injury After Surgical Brain Injury in Rats. (PubMed, Front Surg) - "The results showed that after SBI, LRRK2 and phosphorylated Rab10 (p-Rab10) expression in neuronal cells were upregulated, and administration of PF-06447475 significantly reduced neuronal apoptosis, neuroinflammation, and brain water content 12 h after SBI and improved neurological deficit 72 h after SBI, which is related to the decreased expression of LRRK2 and p-Rab10, and the lessening of lysosomal overload stress. Our research suggests that the inhibition of LRRK2 can effectively interfere with the role of p-Rab10 in promoting the secretion of lysosomal hydrolase in lysosomal overload stress after SBI, thereby reducing neuronal apoptosis and inflammation after SBI and playing a major role in brain protection."

Journal • Preclinical • CNS Disorders • Immunology • Inflammation • Movement Disorders • Parkinson's Disease • Vascular Neurology

Phenolic-rich extract of avocado Persea americana (var. Colinred) peel blunts paraquat/maneb-induced apoptosis through blocking phosphorylation of LRRK2 kinase in human nerve-like cells. (PubMed, Environ Toxicol) - "Our findings imply that CRE protects NLCs directly via antioxidant mechanism and indirectly by blocking LRRK2 kinase against PQ + MB stress stimuli. These data suggest that CRE might be a potential natural antioxidant."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • CASP3

In vivo susceptibility to energy failure parkinsonism and LRRK2 kinase activity. (PubMed, Neurobiol Dis) - "LRRK2 kinase inhibitors PF-06447475 and MLi-2, tested under preventive or therapeutic treatments, protected against nigral dopamine cell loss in G2019S knock-in mice. We conclude that LRRK2 G2019S, likely through enhanced kinase activity, confers greater susceptibility to mitochondrial toxin-induced parkinsonism. LRRK2 kinase inhibitors are neuroprotective in this model."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • GFAP

F-Labelled pyrrolopyrimidines reveal brain leucine-rich repeat kinase 2 expression implicated in Parkinson's disease. (PubMed, Eur J Med Chem) - "With pyrrolopyrimidine derivative PF-06447475 as the lead compound, two in vivo-stable F-labelled pyrrolopyrimidines ([F]1 and [F]2) were synthesized automatically at radiochemical yields 8-10% (non-decay-corrected) with molar activities of 0.95 and 0.5 GBq/μmol, respectively...Parkinson's disease-like deficits in dopamine transporter synthesis and cognitive declines were noticed along with LRRK2 expression increase in the olfactory bulb, striatum, and hippocampus. Therefore, F-labelled pyrrolopyrimidines can reflect real-time LRRK2 expression changes implicated in Parkinson's disease, which paves the way for LRRK2-related neurodegenerative precise therapy."

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

LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. (PubMed, Hum Mol Genet) - "Using the two selective and potent LRRK2 kinase inhibitors, MLi-2 and PF-06447475, we demonstrated that the LRRK2-R1441C-mediated decrease in autolysosome maturation is not dependent on LRRK2 kinase activity. Our work defines a novel interaction between the LRRK2 protein and the vATPase a1 subunit and demonstrates a mode of action by which drugs may rescue lysosomal dysfunction. These results demonstrate the importance of LRRK2 in lysosomal biology, as well as the critical role of the lysosome in PD."

Journal

Investigating the cellular role of LRRK2 in the immune system (MDS Congress 2019) - "We investigated LRRK2 phosphorylation dynamics in RAW264.7 macrophage cell lines (wild-type, T1348N-LRRK2 (artificial mutation that ablates GTP binding) and KO-LRRK2) following stimulation with lipopolysaccharide (LPS) and zymosan and pharmacologically inhibiting with four specific LRRK2 kinase inhibitors, GNE-7915, GNE-9605, MLi-2 and PF-06447475...LPS and zymosan significantly upregulate LRRK2 phosphorylation in wild-type cells with LPS comparatively showing a more sustained upregulation over time. All four specific LRRK2 kinase inhibitors downregulated phosphorylation at Ser935 and Rab8 which are readouts of LRRK2 kinase activity. Our data of aberrant cytokine basal secretion in modified cells indicate the involvement of LRRK2 and inhibitors in the immune processes of macrophages."