Existing treatments for Parkinson's disease (PD), which affects 10 million people worldwide, primarily augment dopaminergic neurotransmission to provide symptomatic benefit. No current therapy can slow or stop the progression of PD. We propose a drug discovery platform to develop small molecules targeting the parkin-USP30 mitophagy pathway, which represents a key regulator of mitochondrial homeostasis. Converging lines of evidence from human genetics, tissue pathology and biochemical studies from sporadic PD patients, and animal model studies indicate that deficits in Mitophagy are a modifiable contributor to PD pathogenesis. Specifically, inhibition or knockdown of the deubiquitinating enzyme USP30 can enhance mitophagy in a variety of cell types and infers neuroprotection in two fruit fly models (pink1 deficiency and paraquat toxicity). However, studies examining neurodegeneration in larger animals such as rodents are an unfilled gap in knowledge that should be addressed prior to development of USP30 inhibitors as therapeutics for PD. In the proposed Aims, we will test the hypothesis that USP30 inhibitor small molecules will protect against neurodegeneration induced by a mitochondrial toxin MPTP, or a-synuclein preformed fibrils - both models with links to Parkinson's disease and mitophagy. Our preliminary data demonstrate that we have generated a series of small molecules that potently and selectively inhibit USP30 activity in vitro, and demonstrate cellular activity without cytotoxicity in differentiated neuronal cell lines. Top compounds have good in vitro ADME properties and a lead and back up compound have been identified with excellent rat and mouse plasma and brain PK profiles which place us in a unique position to examine the proposed hypothesis. If successful, the studies proposed in this application will justify further investment toward development of our small molecules through Investigational New Drug filing (IND)-enabling studies, out-license, or partnership with big pharma or biotech for further clinical development.
Public Health Relevance Statement: NARRATIVE Parkinson's Disease is an age-associated neurodegenerative disorder affecting nearly 1 million Americans, and present treatments provide only symptomatic benefit, with disease progression resulting in diminished efficacy and often intolerable motor complications. Mitochondrial dysfunction is tightly involved in the loss of dopaminergic neurons central to the disease, raising the possibility clearance of damaged mitochondria via increased mitophagy may hold disease modifying benefit. We developed potent and selective USP30 inhibitors that promote mitophagy in cells, which we now propose to evaluate in vivo for their potential as first-in-class therapeutics to stop or slow progression of Parkinson's Disease.
Project Terms: Paraquat; 1, 1'-dimethyl-4, 4'-bipyridinium; Methyl Viologen; Parkinson Disease; Paralysis Agitans; Parkinson; Primary Parkinsonism; Pathology; Patients; Permeability; Drug Kinetics; Pharmacokinetics; Pharmacology; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma Proteins; Rattus; Common Rat Strains; Rat; Rats Mammals; Risk Factors; Rodent; Rodentia; Rodents Mammals; Solubility; Substantia nigra structure; Substantia Nigra; Testing; Tissues; Body Tissues; Toxin; antimycin; Measures; Mediating; pars compacta; Acute; Clinical; Penetration; Biochemical; Series; Link; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Licensing; Disease Progression; Letters; NAC precursor; PARK1 protein; PARK4 protein; SNCA; SNCA protein; a-syn; a-synuclein; alpha synuclein gene; alphaSP22; asyn; non A-beta component of AD amyloid; non A4 component of amyloid precursor; a synuclein gene; a-syn; a-synuclein; alpha synuclein; de-ubiquitinase; de-ubiquitinating enzyme; ubiquitin-specific isopeptidase; ubiquitin isopeptidase; Therapeutic; Genetic; Knowledge; Complex; Clinic; cell type; Neurodegenerative Disorders; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; American; cytotoxicity; Lytotoxicity; success; neuroprotection; neuroprotective; Animal Model; Animal Models and Related Studies; model of animal; Manuscripts; Toxic effect; Toxicities; neurotransmission; Nerve Impulse Transmission; Nerve Transmission; Neuronal Transmission; axon signaling; axon-glial signaling; axonal signaling; glia signaling; glial signaling; nerve signaling; neural signaling; neuronal signaling; novel; Pathogenesis; Positioning Attribute; Position; dopaminergic neuron; DA Neuron; Dopamine neuron; Pharmacodynamics; Modeling; Property; drug discovery; small molecule; Deubiquitinating Enzyme; PINK1 gene; PARK6; PARK6 gene; PARK6 protein; PINK1; PINK1 gene product; PINK1 protein; PTEN induced kinase 1; PTEN induced putative kinase 1; PTEN-induced putative kinase; Parkinson disease 6 gene; Phosphatase and tensin homolog induced kinase 1; protein kinase BRPK; protein kinase BRPK gene; serine/threonine-protein kinase PINK1; LRRK2 gene; LRRK2; LRRK2 leucine-rich repeat kinase 2 gene; LRRK2 protein; PARK8 protein; Parkinson disease 8 protein; dardarin; dardarin gene; dardarin protein; leucine-rich repeat kinase 2; Address; Dose; Data; Disease Pathway; Motor; in vivo; Other Genetics; Neuronal Differentiation; Modification; Development; developmental; Parkin; Parkin gene; parkin protein; Pathway interactions; pathway; age dependent; age related; knockdown; knock-down; multidisciplinary; mitochondrial dysfunction; murine model; mouse model; iPS; iPSC; iPSCs; induced pluripotent cell; inducible pluripotent stem cell; induced pluripotent stem cell; overexpress; overexpression; in vitro activity; Regimen; small molecule inhibitor; nano-molar; nanomolar; FBX7; FBXO7; FBXO7 gene; Idiopathic Parkinson Disease; experiment; experimental research; experiments; experimental study; clinical development; lead candidate; in vivo testing; in vivo evaluation; Differences between sexes; Differs between sexes; Sexual differences; sex-dependent differences; sex-related differences; sex-specific differences; Sex Differences; pre-formed fibril; sporadic Parkinson's Disease; Affect; ages; Age; Animals; inhibitor; Automobile Driving; driving; Autopsy; necropsy; postmortem; Back; Dorsum; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Biology; Biotechnology; Biotech; Brain; Brain Nervous System; Encephalon; Cell Count; Cell Number; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Central Nervous System Diseases; CNS Diseases; CNS disorder; Central Nervous System Disorders; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Clinical Trials; Corpus striatum structure; Corpus Striatum; Striate Body; Striatum; striatal; Disease; Disorder; Dopamine; Hydroxytyramine; Drosophila genus; Drosophila; fruit fly; Investigational Drugs; Investigational New Drugs; Elements; Experimental Designs; Female; Future; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; Human Genetics; In Vitro; Investments; Kinetics; Lead; Pb element; heavy metal Pb; heavy metal lead; Light; Photoradiation; male; Methods; Microsomes; Mitochondria; mitochondrial; Study models; Genetic Models; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Persons; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Oligomycins; Paper
