DYRK1A inhibitors as therapeutic approach to Tau hyper-phosphorylation for treatment of Alzheimer disease and other CNS disorders

Avanti Biosciences, Inc., East Setauket NY

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Abstract

PROJECT SUMMARY The objective of this proposal is to develop potent and selective inhibitors of the kinase, DYRK1A, to treat mild to moderate Alzheimer?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 several 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. DYRK1A is a proline-directed serine/threonine kinase whose activity may be involved in AD pathogenesis because: (1) DYRK1A is a kinase for which tau serves as substrate; (2) it is robustly expressed in CNS neurons; (3) increased DYRK1A immunoreactivity is found in AD in the cytoplasm and nucleus of neurons of the entorhinal cortex, hippocampus and neocortex; (4) its presence there is associated with increased phosphorylation of tau; (5) DYRK1A-induced phosphorylation of tau reduces tau?s ability to stabilize microtubules; and (6) DYRK1A-induced phosphorylation of tau promotes self-aggregation and fibrillization. Significantly, DYRK1A ?primes? tau for additional phosphorylation by GSK3? kinase which is known to contribute to AD pathogenesis. These findings support our hypothesis that inhibition of DYRK1A 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 DYRK1A. Avanti Biosciences is specifically and uniquely focused on DYRK1A and aims to discover small molecule DYRK1A negative modulators derived from natural catechins. The main ingredient of green tea, epigallocatechin gallate (EGCG), is a potent allosteric negative modulator of DYRK1A that results in decreased kinase activity. Unfortunately, EGCG is relatively unstable metabolically and achieves low brain exposure. Our earlier work in this field showed that several other catechin derivatives maintain or improve the activity and improve metabolic stability compared to EGCG. The trans catechin derivatives Gallocatechin gallate (GCG) and Catechin gallate (GC) were among the more potent and more stable catechin tested. To 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 class. We are proposing the synthesis of tetrahydronaphthalene derivatives in which the oxygen atom is replaced by the methylene group in the C-ring. Furthermore, we are proposing the introduction of the more metabolically stable pyrido group in place of the catechin B-ring. Thanks to our previous Structure Activity Relationship (SAR) analysis conducted on catechins, these changes should maintain/improve the activity for the proposed derivatives. New compounds will be validated as negative modulators of DYRK1A activity in vitro and best compound(s) will be studied in the rTg4510 tauopathy in vivo model to monitor tau phosphorylation levels in the brain.