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 kinase DYRK A to treat mild to moderate Alzheimerandapos s disease AD A compelling body of data points to hyperphosphorylated tau species as mediators of toxicity in AD p Tau species may significantly impact a number of cellular events Prominently they participate in the formation of neurofibrillary tangles NFTs whose presence is closely linked with disease progression An important question that remains is how tau is hyperphosphorylated DYRK A is a dual specificity kinase for which tau serves as a substrate DYRK A activity may be involved in AD pathogenesis because DYRK A is a kinase for which tau serves as substrate it is robustly expressed in CNS neurons increased DYRK A immunoreactivity is found in AD in the cytoplasm and nucleus of neurons of the entorhinal cortex hippocampus and neocortex its presence there is associated with increased phosphorylation of tau DYRK A induced phosphorylation of tau reduces tauandapos s ability to stabilize microtubules and DYRK A induced phosphorylation of tau promotes self aggregation and fibrillization Significantly DYRK A `primesandapos tau for additional phosphorylation by GSK kinase which is known to contribute to AD pathogenesis These findings support our hypothesis that inhibition of DYRK A activity will be disease modifying and significantly impact on the lives of those with AD In spite of a role for p tau in AD pathogenesis few pharmaceutical industry efforts are targeting the modulation of DYRK A Avanti Biosciences is specifically and uniquely focused on DYRK A and aims to discover small molecule DYRK A negative modulators derived from natural catechins The main ingredient of green tea epigallocatechin gallate EGCG is a potent allosteric negative modulator of DYRK A that results in decreased kinase activity Unfortunately EGCG is relatively unstable metabolically and achieves low brain exposure To discover new catechins that exert the same activity with improved drug like properties we characterized the catechins in green tea and discovered that EGCG was not the most potent catechin In fact the trans catechin derivatives Gallocatechin gallate GCG and Catechin gallate GC were more potent more stable and may achieve better brain exposure We propose to modify these natural catechins to improve potency metabolic stability and brain bioavailability Selected lead compounds will be validated as negative modulators of DYRK A activity in vitro and in the rTg tauopathy model These studies are intended to support future IND enabling studies of potent negative modulators of DYRK A and eventual AD clinical trials PROJECT NARRATIVE Tau hyperphosphorylation triggers synaptic dysfunction and formation of neurofibrillary tangles NFTs both of which feature in the pathogenesis of Alzheimerandapos s disease AD Treatments that reduce tau phosphorylation are hypothesized to block and potentially reverse pathogenesis and disease progression Avanti Biosciences is pioneering the development of potent negative allosteric modulators of DYRK A a kinase that phosphorylates tau and whose activity is plausibly linked to p tau mediated synaptic and neuronal dysfunction and death in AD In collaboration with NY Institute for Basic Research Avanti has identified catechins that negatively modulate the activity of DYRK A suggesting that potent allosteric inhibition of DYRK A can be achieved The requested funding will enable preparation and testing of potent new catechin analogs of these small molecules with improved metabolic stability and brain bioavailability These early studies will facilitate future work to optimize and develop advanced compounds for preclinical studies and eventual AD clinical trials An 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