Objective/Rationale:
Previously inhibitors of mixed lineage kinase 3 (MLK3) showed great promise for treatment of Parkinson’s disease in pre-clinical models, but interest in this area halted when a potent inhibitor (CEP-1347) failed in Phase II clinical trials. We have investigated the target specificity and ability of CEP-1347 to penetrate the blood-brain barrier and have developed a new compound with much higher specificity for MLK3 and much improved ability to achieve high concentrations in the brain.
Project Description:
We will verify the ability of the new compound, CLFB-1134, to achieve sustained therapeutic brain concentrations in pre-clinical models and then test the efficacy of the compound to protect against 6-hydroxydopamine, a neurotoxin that depletes dopamine. We will measure target engagement in the brain and the protective effects of CLFB-1134 using behavioral, neurochemical and immunohistological outcome measures.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current treatments for Parkinson’s disease attempt to treat symptoms by increasing the supply of dopamine in areas of the brain where dopaminergic neurons and their associated neural circuitry are being destroyed. Success in the model would be a first step towards finding agents that minimize the negative impact of brain inflammation to prevent or slow destruction of dopaminergic neurons and halt or at least slow the disease progression.
Anticipated Outcome:
Improvement of our experimental outcomes in the pre-clinical model with CLFB-1134 would provide significant evidence that MLK3 is a validated target for Parkinson’s disease since the compound inhibits only a small fraction of the protein kinases inhibited by CEP-1347. CLFB-1134 could serve as a prototype development compound as it has an excellent in vitro safety profile. Compound failure in this model would suggest that a broader acting kinase inhibitor that hits multiple targets may be of interest for future research.
Final Outcome
We verified the ability of CLFB-1134 to achieve sustained therapeutic brain concentrations in mice. We then explored the ability of CLFB-1134 to protect dopaminergic neurons from the effects of MPTP, a compound which causes symptoms similar to Parkinson’s disease in humans and mice. We measured the ability of CLFB-1134 to protect neurons in the substantia nigra and striatal terminals when given simultaneously with MPTP or after the chemical toxin. We found that CLFB-1134 dosed along with or after MPTP injections protects against MPTP-induced dopaminergic degeneration. As with many other agents that protect against dopaminergic neuron death in the MPTP model, there was little effect on preservation of dopamine levels in striatal terminals. We confirmed CLFB-1134 attenuates signaling of the JNK/c-jun cell death pathway. Future experiments will focus on determining whether the dopaminergic neuron preserving effects of CLFB-1134 warrant testing as a drug candidate.