SBIR-STTR Award

Research & Related Other Project Information Item 7. Project Summary/Abstract Neurodegeneration in Alzheimer's disease (AD) may result from deposition of A¿ as plaques in brain tissue. However, less effort has been made to elucidate the role of tau- containing neurofibrillary tangles (NFTs) in AD. Accumulating evidence suggests that tau containing NFTs is an important component in the initiation and progression of AD and other neurodegenerative diseases. In this proposal the tau pathway is targeted through inhibition of the molecular chaperone Hsp90 as a promising new approach to affect the disease progression of AD. The goal of this grant is to optimize two structurally distinct scaffolds aided by in silico modeling and physical-chemical property predictions in order to generate novel brain permeable Hsp90 inhibitors as AD therapeutics. Subsequently, these compounds will be clinically developed for the treatment of AD using CSF biomarkers, as well as improved cognition, for in vivo efficacy determinations.

Public Health Relevance:
Research & Related Other Project Information Item 8. Project Narrative This research is focused on identifying potential drug candidates to treat Alzheimer's disease (AD) and in this way it addresses NIA's priorities to support research on health and disease in the aged. Furthermore, this project targets the tau pathway as a promising new approach to affect the disease progression of AD.

Public Health Relevance Statement:
Research & Related Other Project Information Item 8.

NIH Spending Category:
Aging; Alzheimer's Disease; Brain Disorders; Neurodegenerative; Neurosciences

Project Terms:
abnormally phosphorylated tau; abstracting; Accounting; addiction; Affect; Affinity; Alzheimer's Disease; Amyloid; base; Binding (Molecular Function); Biochemical; Biological Assay; Biological Markers; Brain; brain tissue; Cell Death; Cell model; Cells; Cerebrospinal Fluid; chemical property; Chromosomes, Human, Pair 17; Clinical; Clinical Trials; Cognition; Communication; Complex; Computer Simulation; Cyclin-Dependent Kinases; cytotoxicity; Dementia; Dependence; Deposition; design; Development; Disease; Disease Outcome; Disease Progression; Dissociation; Dose; drug development; drug discovery; Frontotemporal Dementia; Genes; Glycogen Synthase Kinase 3; Goals; Grant; heat-shock factor 1; Heat-Shock Proteins 90; HSP 90 inhibition; improved; In Vitro; in vivo; Inherited; inhibitor/antagonist; Inhibitory Concentration 50; Link; Measures; Medical; Microtubules; mild neurocognitive impairment; Molecular Chaperones; Molecular Target; Mutation; neoplastic cell; Nerve Degeneration; neuroblastoma cell; Neurodegenerative Disorders; neurofibrillary tangle formation; Neurofibrillary Tangles; Neurons; Normal Cell; novel; novel strategies; oncology; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; physical model; Play; Population Study; Proteins; Relative (related person); Research; Role; scaffold; secretase; Senile Plaques; Severities; Solubility; Structure; Structure-Activity Relationship; System; tau aggregation; tau mutation; tau phosphorylation; tau Proteins; tau-1; Testing; Therapeutic; Therapeutic Agents; Tissues; tumor

Neurodegeneration in Alzheimer's disease (AD) may result from deposition of Aβ as plaques in brain tissue. However, less effort has been made to elucidate the role of tau- containing neurofibrillary tangles (NFTs) in AD. Accumulating evidence suggests that tau containing NFTs is an important component in the initiation and progression of AD and other neurodegenerative diseases. In this proposal the tau pathway is targeted through inhibition of the molecular chaperone heat shock protein 90 (Hsp90) as a promising new approach to affect the disease progression of AD. This proposal builds on the specific aims set forth and achieved under the STTR Phase I funding - a) to conduct structure-activity relationship studies to obtain brain permeable Hsp90 inhibitors and b) to evaluate biochemical and cellular Hsp90 inhibition. These efforts yielded novel, proprietary Hsp90 inhibitors with acceptable drug-like properties including good brain concentration. Since the conclusion of Phase I funding, Yuma Therapeutics has generated pharmacokinetic data in mice for an early lead compound, YT-17, further supporting its drug-like properties. The proposed studies for Phase II focus on a) evaluating our lead compound in an in vivo transgenic mouse model of tauopathy on the levels of total tau and phosphorylated-tau in cerebrospinal fluid, tau neuropathology, and behavioral outcomes; b) manufacturing scale-up of active pharmaceutical ingredient (API) of a lead candidate and initiate in vivo toxicology studies; and c) formulation work on the API.

Public Health Relevance Statement:


Public Health Relevance:
This research is focused on identifying potential drug candidates to treat Alzheimer's disease (AD) and in this way it addresses NIA's priorities to support research on health and disease in the aged. Furthermore, this project targets the tau pathway as a promising new approach to affect the disease progression of AD.

Project Terms:
abnormally phosphorylated tau; Address; Affect; Aftercare; aged; Alzheimer's Disease; Amygdaloid structure; Amyloid beta-Protein; anticancer research; Award; Back; behavior measurement; Behavioral; Biochemical; Biological Assay; Biological Markers; Brain; brain tissue; cancer therapy; Cerebrospinal Fluid; Clinical; Clinical Treatment; Cyclin-Dependent Kinases; Data; Deposition; Deterioration; Development; Disease; Disease Progression; Dose; drinking water; drug candidate; Drug Formulations; Drug Kinetics; Funding; Generations; Health; Heat Stress Disorders; Heat-Shock Proteins 90; Hippocampus (Brain); HSP 90 inhibition; Human; improved; In Vitro; in vivo; Individual; inhibitor/antagonist; Investigational New Drug Application; Lead; Learning; manufacturing scale-up; Measurement; Memory; mild cognitive impairment; Molecular Chaperones; Monitor; morris water maze; mouse model; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; neuropathology; novel; novel strategies; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; phase 2 study; Property; protein degradation; Proteins; Publishing; Regimen; Reporting; Research; Research Support; Role; Running; Safety; selenate; Small Business Technology Transfer Research; Sodium; Solubility; Structure-Activity Relationship; tau aggregation; tau mutation; tau phosphorylation; tau Proteins; tau-1; Tauopathies; Therapeutic; therapy development; Time; TimeLine; Tissues; Toxicology; Transgenic Mice; transgenic model of alzheimer disease; treatment effect; tumor growth; Validation; Variant; Work