Preclinical evaluation of the anti-neuroinflammatory properties and pharmacokinetic profile of a novel Fyn kinase inhibitors

ABSTRACTParkinsonandapos s diseasePDis a debilitating neurodegenerative disorder characterized mainly by the progressive loss of dopaminergic neurons in the substantia nigra pars compactaSNpcresulting in severe neurological deficitsThe existing approaches to PD treatment are focused mainly on alleviating motor symptoms by compensating for neurochemical deficitsbut such treatment fails to halt progression of the neurodegenerative processThe lack of effective neuroprotective drugs for PD is primarily attributed to a limited understanding of the complex mechanisms involved in the degenerative processes of the nigral dopaminergic systemHoweverrecent discoveries about cell death pathways and oxidative stress signaling have offered some important clues that boost hope for the development of novel mechanism based neuroprotective strategies for PDIn this regardwe have demonstrated that oxidative stress triggers the mitochondrially mediated caspase cascade and Fyn kinase activation to induce neuronal cell deathcell culture and animal models of neurodegenerationFurthermoreFyn knockout mice are resistant to MPTP induced behavioral deficitsneurochemical depletionand nigral dopaminergic neuronal damageVery recentlywe observed that Fyn kinase is rapidly activated and mediates LPSandSynPFF induced increases in nitrite and proinflammatory cytokine production in cell culture and animal models of neuroinflammationCollectivelythese mechanistic studies reveal that Fyn is a key upstream proapoptotic kinase involved in neuroinflammationand as suchit could prove to be a promising therapeutic target for PDImportantlywe screened andgtcompounds from the focused kinase CP library belonging todifferent scaffolds against human Fyn kinaseThis resulted in identification of nine compounds with andgtinhibition of human Fyn kinase activityThe best among theseCPand CPbelonging todifferent scaffoldsexhibited an ICofnM for human Fyn inhibitionA dose response study revealed that CP analogs inhibited LPSandSynPFF induced increases in nitriteICrangeMand proinflammatory cytokine productionunlike the AZDFyn kinase inhibitorwhich in clinical trials failed to inhibit even atMTo capitalize on these discoveries and to demonstrate proof of principlewe are proposing PKCNS bioavailabilitymetabolic stability and preclinical efficacy studies of CPand CPin this SBIR Pexploratory application prior to developing CP analogs with an exceptionally lownanomolar ICfor Fynas well as preclinical toxicology and safety studiesThe combination of a validated therapeutic targetintegrated study design and demonstrated expertise will help us accomplish these important goalsWe anticipate that these CP analogs would advance to pharma fingerprintHERGCYPdose formulationspreclinical toxicological and safety evaluations in SBIR PII grant applicationsThe overall approach is expected to result in a new class of disease modifying drugs for PDA joint WTO patent application between ChemVeda and PK Biosciences has been filed NoNARRATIVE Existing therapies to treat neurodegenerative diseasessuch as Parkinsonandapos s diseasePDfocus mainly on treating symptoms rather than halting disease progressionRecent mechanistic studies indicate that Fyn kinase activation contributes to neurodegenerative processes in PDThusin this proof of concept studywe will validate tri heterocyclic small molecule inhibitors of Fyn kinase as novel anti neuroinflammatory agents for treating neurodegenerative disorders