We have identified a small molecule, designated J3, which shows promising neuroprotection in an acute animal model of Parkinson’s disease (PD). To reach our ultimate goal of developing a disease-modifying drug for PD, we need to generate analogs with better potency and selectivity than J3. To facilitate this effort, we propose to identify the cellular processes and components that are altered by J3 and use this information to implement biochemical assays for compound potency and selectivity, thereby accelerating the optimization of the J compound series.
J3 was originally identified in cellular PD models by its ability to rescue the toxicity of alpha-synuclein (asyn), a protein associated with PD. Using biochemical assays, we recently learned that J3 inhibits a class of enzymes called lipid kinases, suggesting that a member of this protein family mediates the toxicity of asyn. The goals of the proposed study is to identify which lipid kinase is most strongly inhibited by J3 and prove using genetic methods that this lipid kinase plays a role in asyn toxicity in cells.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The J series is neuroprotective in a new animal model in which the overexpression of alpha-synuclein, a protein that is a causative factor in PD, kills dopamine producing neurons in the substantia nigra, the area of the brain that is destroyed by PD. Knowing how J3 achieves its effect will facilitate development of more potent analogs, accelerating the selection of a drug candidate. In addition, this work may identify cellular pathways and/or proteins that can be modulated to protect cells from the toxicity of alpha-synuclein, providing new targets for neuroprotective agents for PD.
We expect to prove or disprove that a lipid kinase is a target for rescuing asyn toxicity in cells.
We identified two targets of the J series. A subset of J compounds inhibit the TOR pathway; this is unlikely to be the mechanism of alpha-synuclein rescue but may explain the cytoxicity observed in some compounds. J compounds potently inhibit CK1 epsilon with some activity against delta. Additional studies are required to determine if this is the mechanism of alpha-synuclein rescue.