Avanti Biosciences Inc — Department of Health and Human Services SBIR Phase I: NIA

Description

PROJECT SUMMARY The objective of this proposal is to develop potent and selective inhibitors of the kinaseDYRK Ato treat mild to moderate Alzheimer s diseaseADA compelling body of data points to hyperphosphorylated tau species as mediators of toxicity in ADp Tau species may significantly impact several cellular eventsProminentlythey participate in the formation of neurofibrillary tanglesNFTswhose presence is closely linked with disease progressionAn important question that remains is how tau is hyperphosphorylatedDYRK A is a proline directed serine threonine kinase whose activity may be involved in AD pathogenesis becauseDYRK A is a kinase for which tau serves as substrateit is robustly expressed in CNS neuronsincreased DYRK A immunoreactivity is found in AD in the cytoplasm and nucleus of neurons of the entorhinal cortexhippocampus and neocortexits presence there is associated with increased phosphorylation of tauDYRK A induced phosphorylation of tau reduces tau s ability to stabilize microtubulesandDYRK A induced phosphorylation of tau promotes self aggregation and fibrillizationSignificantlyDYRK Aprimestau for additional phosphorylation by GSKkinase which is known to contribute to AD pathogenesisThese findings support our hypothesis that inhibition of DYRK A activity will be disease modifying and significantly impact on the lives of those with ADIn spite of a role for p tau in AD pathogenesisfew pharmaceutical industry efforts are targeting the modulation of DYRK AAvanti Biosciences is specifically and uniquely focused on DYRK A and aims to discover small molecule DYRK A negative modulators derived from natural catechinsThe main ingredient of green teaepigallocatechin gallateEGCGis a potent allosteric negative modulator of DYRK A that results in decreased kinase activityUnfortunatelyEGCG is relatively unstable metabolically and achieves low brain exposureOur earlier work in this field showed that several other catechin derivatives maintain or improve the activity and improve metabolic stability compared to EGCGThe trans catechin derivatives Gallocatechin gallateGCGand Catechin gallateGCwere among the more potent and more stable catechin testedTo further improve their chemical metabolic stability we are now proposing the synthesis of few derivatives which modify key groups that we found are responsible for the rapid metabolism and instability of this classWe are proposing the synthesis of tetrahydronaphthalene derivatives in which the oxygen atom is replaced by the methylene group in the C ringFurthermorewe are proposing the introduction of the more metabolically stable pyrido group in place of the catechin B ringThanks to our previous Structure Activity RelationshipSARanalysis conducted on catechinsthese changes should maintain improve the activity for the proposed derivativesNew compounds will be validated as negative modulators of DYRK A activity in vitro and best compound swill be studied in the rTgtauopathy in vivo model to monitor tau phosphorylation levels in the brain PROJECT NARRATIVE Alzheimer s diseaseADis a devastating neurological disorder and is currently estimated to affectmillion AmericansInAD and other related dementias will cost the United States $billionand if the current disease trajectory is maintainedthe associated costs could rise to as high as $trillion byAD is the only top ten cause of death in America that cannot be preventedcured or slowedand thus there is an urgent medical need for disease modifying therapeutic agentsTau hyperphosphorylation triggers synaptic dysfunction and formation of neurofibrillary tanglesNFTsboth of which feature in the pathogenesis of ADTreatments that reduce tau phosphorylation are hypothesized to block and potentially reverse pathogenesis and disease progressionAvanti Biosciences is pioneering the development of potent negative allosteric modulators of DYRK Aa kinase that phosphorylates tau and whose activity is believed to be linked to p tau mediated synaptic and neuronal dysfunction and death in ADIn collaboration with NYS Institute for Basic ResearchAvanti has identified catechins that negatively modulate the activity of DYRK Asuggesting that potent allosteric inhibition of DYRK A can be achievedThe requested funding will enable preparation and testing of potent new catechin analogs of these small molecules with improved metabolic stability and brain bioavailabilityThese early studies will facilitate future work to optimize and develop advanced compounds for preclinical studies and eventual clinical trialsAn optimized DYRK A kinase modulator IND candidate that reduces tau phosphorylation would significantly expand the portfolio of treatments to reverse AD symptoms and block disease progression