The objective of this proposal is to develop potent and selective inhibitors of the kinase, DYRK1A, to treat mild to moderate Alzheimerâs 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 tauâs ability to stabilize microtubules; and (6) DYRK1A-induced phosphorylation of tau promotes self-aggregation and fibrillization. Significantly, DYRK1A âprimesâ tau for additional phosphorylation by GSK3β 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.
Public Health Relevance Statement: PROJECT NARRATIVE Alzheimerâs disease (AD) is a devastating neurological disorder and is currently estimated to affect 5.5 million Americans. In 2017, AD and other related dementias will cost the United States $259 billion, and if the current disease trajectory is maintained, the associated costs could rise to as high as $1.1 trillion by 2050. AD is the only top ten cause of death in America that cannot be prevented, cured or slowed, and thus there is an urgent medical need for disease modifying therapeutic agents. Tau hyperphosphorylation triggers synaptic dysfunction and formation of neurofibrillary tangles (NFTs), both of which feature in the pathogenesis of 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 believed to be linked to p-tau mediated synaptic and neuronal dysfunction and death in AD. In collaboration with NYS 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 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: ABCB1 gene; Acute; Affect; Alzheimer's Disease; American; Americas; analog; Animals; base; Basic Science; Binding Proteins; Biological; Biological Assay; Biological Availability; Biological Sciences; Blood; Blood - brain barrier anatomy; Brain; Bypass; carbene; Catechin; Cause of Death; Cell Nucleus; Central Nervous System Diseases; Chemicals; clinical development; Clinical Trials; cognitive function; Collaborations; cost; Cytoplasm; Data; Dementia; Deposition; design; Development; Disease; Disease Progression; Dose; Drug Industry; Drug Kinetics; efficacy testing; entorhinal cortex; Epigallocatechin Gallate; Event; experience; Filament; Formulation; Functional disorder; Funding; Future; gallocatechol; Green tea; Half-Life; Hippocampus (Brain); Human; Hydroxyl Radical; hyperphosphorylated tau; immunoreactivity; improved; In Vitro; in vitro activity; in vivo; in vivo evaluation; in vivo Model; inhibitor/antagonist; Institutes; Intercept; kinase inhibitor; Lead; lead optimization; Link; Liver; MDCK cell; Measures; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolism; Microsomes; Microtubule Stabilization; Modeling; Modification; Monitor; Mus; Neocortex; nervous system disorder; neurofibrillary tangle formation; Neurofibrillary Tangles; neuron loss; Neuronal Dysfunction; Neurons; novel; Oral; overexpression; Oxygen; Pathogenesis; Pathologic; Penetration; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Plasma; Plasma Proteins; preclinical study; Preparation; prevent; Proline; Property; Protein-Serine-Threonine Kinases; pyridine; Reporting; Role; Safety; small molecule; Source; Specificity; Structure; Structure-Activity Relationship; Symptoms; Synapses; Synaptic plasticity; tau phosphorylation; tau Proteins; tau-1; Tauopathies; Testing; Tetrahydronaphthalenes; Therapeutic; Therapeutic Agents; therapeutic evaluation; Toxic effect; Tyrosine; United St
