Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor

Henderson, Jaclyn L.; Kormos, Bethany L.; Hayward, Matthew M.; Coffman, Karen J.; Jasti, J.; Kurumbail, Ravi G.; Wager, Travis T.; Verhoest, Patrick R.; Noell, G; Chen, Yi; Needle, Elie; Berger, Zdenek; Steyn, Stefanus J.; Houle, Christopher; Hirst, Warren D.; Galatsis, Paul

doi:10.1021/jm5014055

Cited by 155 publications

(164 citation statements)

References 42 publications

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“…Although there are multiple kinase inhibitors available that target mutant forms of LRRK2, the search for new potent WT LRRK2 kinase inhibitors is much needed for future studies investigating LRRK2 phosphorylation in sporadic PD. The recently developed LRRK2 kinase inhibitor 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475) holds promise for the treatment of sporadic PD since it has a high affinity to target WT LRRK2 and has been validated for use in vivo [46]. …”

Section: Discussionmentioning

confidence: 99%

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

et al. 2015

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It has been uncertain whether specific disease-relevant biomarker phenotypes can be found using sporadic Parkinson’s disease (PD) patient-derived samples, as it has been proposed that there may be a plethora of underlying causes and pathological mechanisms. Fibroblasts derived from familial PD patients harboring leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), and Parkin mutations show clear disease-relevant mitochondrial phenotypes, which are exacerbated under conditions of pharmacological stress. We utilized fibroblasts derived from non-familial sporadic PD patients (without LRRK2 mutations) or LRRK2 mutation carriers to directly compare the cellular phenotypes during and after mitochondrial stress. We then determined the effects of pharmacological LRRK2 kinase inhibition using LRRK2-in-1. We found that there were two distinct populations of sporadic PD patient-derived fibroblast lines. One group of sporadic PD lines was highly susceptible to valinomycin-induced mitochondrial depolarization, emulating the mutant LRRK2 phenotype. These lines showed elevated mitochondrial superoxide/ nitric oxide levels, displayed increased mitochondrial and lysosome co-localization, and an increased rate of mitochondrial collapse, which corresponded with changes in mitochondrial fission and fusion proteins. The application of LRRK2-in-1 reversed decreased levels of mitochondrial and lysosome co-localization and partially restored mitochondrial network associated proteins and the mitochondrial membrane potential in the fibroblasts. This study identifies novel mitochondrial biomarkers in sporadic PD patient-derived fibroblast lines, which could be used as preclinical tools in which to test novel and known neuroprotective compounds.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9435-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

et al. 2015

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“…Its ability to inhibit LRRK2 in vivo reveals that it can cross the BBB. Since its description in 2012, several novel, selective, and brain-penetrating LRRK2 inhibitors have been described, including GSK2578215A [60], GNE-7915 [61], JH-II-127 [62], PF-06447475 [63], and MLi-2 (Table 1 for further details) [64]. These next-generation LRRK2 inhibitors exhibit improved potency, selectivity, and brain penetrability, all of which are important for clinical application.…”

Section: Lrrk2 As a Therapeutic Targetmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Chen¹,

Chen²,

Pu³

2018

Eur Neurol

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Background: Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Summary: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment.

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“…The only MST3-inhibitor co-crystal structuresk nownw ere solved with staurosporine( PDB ID:3 CKX, no associated publication) and as et of recently disclosedp yrrolopyrimidine inhibitors of leucine-rich repeatk inase 2( LRRK2), for which MST3 served as as urrogate. [12] In this work we screenedM ST3 against al ibrary of diverse kinase inhibitors using differentials canning fluorimetry (DSF) and confirmed 14 compounds as MST3 inhibitors by Xray crystallography.T hese inhibitors comprise nine distinct chemicalscaffolds, and the provided structure-activity relationship (SAR) information may serve as af ramework for the rational design of MST3-selective inhibitors as chemical probes and potentialcancertherapeutics.…”

Section: Introductionmentioning

confidence: 84%

Discovery of Diverse Small‐Molecule Inhibitors of Mammalian Sterile20‐like Kinase 3 (MST3)

et al. 2016

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Increasing evidence suggests key roles for members of the mammalian Sterile20-like (MST) family of kinases in many aspects of biology. MST3 is a member of the STRIPAK complex, the deregulation of which has recently been associated with cancer cell migration and metastasis. Targeting MST3 with small-molecule inhibitors may be beneficial for the treatment of certain cancers, but little information exists on the potential of kinase inhibitor scaffolds to engage with MST3. In this study we screened MST3 against a library of 277 kinase inhibitors using differential scanning fluorimetry and confirmed 14 previously unknown MST3 inhibitors by X-ray crystallography. These compounds, of which eight are in clinical trials or FDA approved, comprise nine distinct chemical scaffolds that inhibit MST3 enzymatic activity with IC50 values between 0.003 and 23 μm. The structure-activity relationships explain the differential inhibitory activity of these compounds against MST3 and the structural basis for high binding potential, the information of which may serve as a framework for the rational design of MST3-selective inhibitors as potential therapeutics and to interrogate the function of this enzyme in diseased cells.

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Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor

Cited by 155 publications

References 42 publications

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

Fibroblast Biomarkers of Sporadic Parkinson’s Disease and LRRK2 Kinase Inhibition

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Discovery of Diverse Small‐Molecule Inhibitors of Mammalian Sterile20‐like Kinase 3 (MST3)

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