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 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. DYRK1A is a dual specificity kinase for which tau serves as a substrate. DYRK1A 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. 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 DYRK1A activity in vitro and in the rTg4510 tauopathy model. These studies are intended to support future IND enabling studies of potent negative modulators of DYRK1A and eventual AD clinical trials.
Public Health Relevance Statement: PROJECT NARRATIVE Tau hyperphosphorylation triggers synaptic dysfunction and formation of neurofibrillary tangles (NFTs), both of which feature in the pathogenesis of Alzheimer'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 DYRK1A, 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 DYRK1A, suggesting that potent allosteric inhibition of DYRK1A 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 DYRK1A kinase modulator IND candidate that reduces tau phosphorylation would significantly expand the portfolio of treatments to reverse AD symptoms and block disease progression.
Project Terms: Acute; Adaptive Behaviors; Adenosine Triphosphate; Alzheimer's Disease; analog; Animals; base; Basic Science; Behavior; Binding Proteins; Biological; Biological Assay; Biological Availability; Biological Sciences; Brain; Caco-2 Cells; Canis familiaris; Catechin; Cell Nucleus; Chromosome abnormality; clinical development; Clinical Trials; Cognition; cognitive function; cognitive performance; Collaborations; Cytoplasm; Data; Deposition; design; Development; Disease; Disease Progression; Dose; Down Syndrome; Drug Industry; Drug Kinetics; efficacy study; entorhinal cortex; Epigallocatechin Gallate; Evaluation; Event; Filament; Foundations; Functional disorder; Funding; Future; gallocatechol; genotoxicity; Green tea; Hepatocyte; Hippocampus (Brain); Human; hydroxyl group; hyperphosphorylated tau; immunoreactivity; improved; In Vitro; in vitro activity; in vivo; inhibitor/antagonist; Institutes; Intercept; kinase inhibitor; Lead; Legal patent; Link; Measures; Mediating; Mediator of activation protein; memory recognition; Metabolic; Microsomes; Microtubule Stabilization; Modeling; Monkeys; mouse model; Mus; Neocortex; neurofibrillary tangle formation; Neurofibrillary Tangles; neuron loss; Neuronal Dysfunction; Neurons; novel; Oral; overexpression; oxidation; Pathogenesis; Pathologic; Penetration; Permeability; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphorylation; Phosphotransferases; preclinical development; preclinical study; Preparation; Property; Rattus; Reporting; Risk-Benefit Assessment; Role; Safety; safety study; safety testing; scale up; small molecule; Solubility; Source; Specificity; Structure; Symptoms; Synapses; Synaptic plasticity; tau phosphorylation; tau Proteins; tau-1; Tauopathies; Testing; therapeutic evaluation; Time; Tissues; Toxic effect; Tyrosine; Visual; Work; young adult
