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Grant

DYRK1A Inhibition as a Novel Treatment Approach for Alzheimer's Disease

Sponsored by National Institute on Aging

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$3M Funding
3 People
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Abstract

Alzheimer's disease (AD) is an increasingly common and devastating neurodegenerative disease withno available disease-modifying treatments. Most treatment approaches attack a single disease componenteither the -amyloid or tau protein pathways for example. However pleiotropic interventions will likely beneeded. The dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) protein represents onesuch target with activity in -amyloid tau and neuroinflammatory pathways. Each of these pathwayscontributes to neurodegeneration and cognitive deficits in AD. As such compounds that inhibit Dyrk1a offer apromising new therapeutic approach through novel simultaneous modulation of tau amyloid andneuroinflammatory pathways. To this end our medicinal chemistry efforts have delivered a potent and brainpenetrant molecule Dyr219 which upon dosing in the 3xTg-AD model improves behavioral and both tau andamyloid neuropathological features of AD with no overt adverse effects (Branca et al. Aging Cell 2017 16(5)1146-1154). In a recent extended 6-month study we observe no motor effects in wild-type or 3xTg-AD micefollowing chronic daily dosing and larger reductions to insoluble hyperphosphorylated tau neurofibrillarytangles and insoluble A42 peptides and amyloid plaques. Recently we have confirmed that Dyr219 also triggers Dyrk1a protein degradation assigned to inhibition of the Dyrk1a autophosphorylation process. This effect reduces levels of active Dyrk1A in vivo contributing to efficacy and pointing to a PK-PD relationship between Dyr219 brain exposure and robust neuropathological effects. Ongoing medicinal chemistry efforts directed at enhancement of oral bioavailability and kinome selectivity have recently delivered significantly improved analogs (Dyr476: F% 73% B/P 0.39) and (DYR533: F% 100% B/P 0.30 S(35)-selectivity score 0.03). Importantly Samumed has recently announced the discovery of SM07883 an IND-ready potent oral Type 1 Dyrk1a inhibitor which exhibits significant tau pathologyreduction in JNPL3 mice. We feel the latter validates the feasibility of our short-term pre-clinical hypothesis andsupports the necessity of the aims described herein. In summary we propose a robust medicinal chemistry pipeline coupled with in vivo testing of promising compounds in mice with the aim of delivering molecules superior to Dyr219 that address oral bioavailability are deemed safe in pre-clinical toxicology models and recapitulate its in vivo effects. We expect our new molecules to be effective at modifying the course of pathology and cognitive decline in AD.

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