PF-06685360 / Pfizer - LARVOL DELTA

Development of two pyrrolo-pyridine and -pyrimidine LRRK2 selective PET radioligands (EANM 2024) - "ARG blocking experiments were performed using cold 1 and a LRRK2-specific ligand PFE-360 (US patent US20140005183)... The radiolabeling of [18F]1 and [18F]2 was successful. However, subsequent PET imaging, including displacement experiments, revealed low specific binding in the cynomolgus brain. Consequently, these radioligands are unlikely to be suitable for LRRK2 imaging in vivo using PET."

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

Knocking out the LRRK2 gene increases sensitivity to wavelength information in rats. (PubMed, Sci Rep) - "Differences in VEP amplitudes and latencies were robust and barely impacted by the presence of the LRRK2 inhibitor PFE360, suggesting a developmental effect. Taken together, these results indicate that alterations in visual processing were related to developmental deficiency of LRRK2 and not acute deficiency of LRRK2, indicating a role of LRRK2 in the functional development of the visual system and synaptic transmission."

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

Phenotypic Profiling of Human Stem Cell-Derived Midbrain Dopaminergic Neurons. (PubMed, J Vis Exp) - "Both cell lines were treated with the LRRK2 kinase inhibitor PFE-360 and phenotypic changes were measured. Additionally, we demonstrate how multidimensional phenotypic profiles can be analyzed using clustering or machine learning-driven supervised classification methods. The described protocol will particularly interest researchers working on neuronal disease modeling or studying chemical compound effects in human neurons."

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

Highly potent LRRK2 inhibitors show different potencies, kinetic properties and cellular activities on WT vs. G2019S LRRK2 (Neuroscience 2021) - "In conclusion, these results suggest that the highly potent LRRK2 inhibitors MLi-2 and PFE-360 have differential activities and kinetic binding properties on WT vs. G2019S LRRK2. Furthermore, a differential inhibition of the pS935 and pS1292 sites on WT LRRK2, as observed with GNE-7915 and LRRK2-in-1, suggests that the two phosphorylation sites might be differently modulated by LRRK2 inhibitors."

CNS Disorders • Parkinson's Disease

Treatment of rotenone-induced Parkinsonism in G2019S*LRRK2 knock-in rats with LRRK2 inhibitor PF-06685360 (Neuroscience 2021) - "This report highlights animal model utility for detecting neuroprotective efficacy and genetic interactions. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed."

Preclinical • CNS Disorders • Parkinson's Disease

Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein. (PubMed, Acta Neuropathol Commun) - "We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD."

Journal • CNS Disorders • Cognitive Disorders • Hypotension • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

Genetic background influences LRRK2-mediated Rab phosphorylation in the rat brain. (PubMed, Brain Res) - "Oral administration of the PFE-360 LRRK2 kinase inhibitor fails to provide neuroprotection from dopaminergic neurodegeneration caused by rAAV2/1-mediated overexpression of A53T-αsynuclein in Sprague Dawley rats. These results highlight substantial differences in LRRK2-mediated Rab10 and Rab12 phosphorylation in commonly utilized rat genetic backgrounds and suggest LRRK2 may not play a central role in Rab phosphorylation or mutant αsynuclein toxicity in Sprague Dawley rats."

Journal • CNS Disorders

Exosome markers of LRRK2 kinase inhibition. (PubMed, NPJ Parkinsons Dis) - "In this study, two different brain-penetrant and selective LRRK2 small-molecule kinase inhibitors (PFE-360 and MLi2) were orally administered to groups of cynomolgus macaques. LRRK2 kinase inhibition led to reductions in exosome-LRRK2 protein and the LRRK2-substrate pT73-Rab10 in urine, as well as reduced exosome-LRRK2 and autophosphorylated pS1292-LRRK2 protein in CSF. We propose orthogonal markers for LRRK2 inhibition in urine and CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics."

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

Simplified Brain Organoids for Rapid and Robust Modeling of Brain Disease. (PubMed, Front Cell Dev Biol) - "Treatment with the LRRK2 inhibitor, PFE-360, relieved the phenotype of Parkinson's disease in midbrain-like simBOs. Taken together, these approaches could be applied to large-scale disease models and alternative drug-testing platforms."

Journal • CNS Disorders • Developmental Disorders • Movement Disorders • Parkinson's Disease • YAP1

Classification of α-synuclein-induced changes in the AAV α-synuclein rat model of Parkinson's disease using electrophysiological measurements of visual processing. (PubMed, Sci Rep) - "Inhibition of leucine-rich repeat kinase using PFE360 failed to rescue the VEP delay and instead increased the latency of the VEP waveform. A support vector machine classifier accurately classified rats according to their `disease state' using frequency-domain data from steady-state visual evoked potentials (SSVEP). Overall, these findings indicate that the latency of the rodent VEP is sensitive to changes mediated by the increased expression of α-synuclein and especially when full overexpression is obtained, whereas the SSVEP facilitated detection of α-synuclein across reflects all stages of PD model progression."

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

Long-term exposure to PFE-360 in the AAV-α-synuclein rat model: findings and implications. (PubMed, eNeuro) - "Preclinical in vivo evidence of a beneficial effect of LRRK2 inhibition is mixed and limited. This study increases our understanding but underlines the complexity of LRRK2 as a mediator of neuronal dysfunction; importantly, the present findings further outline some of the limitations inherent to the PD model used, and warrant additional preclinical studies in animal models with better relevance to the clinical pathophysiology to draw conclusion on the therapeutic potential of LRRK2 modulation in PD."

Journal • Preclinical • CNS Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease