SBIR-STTR Award

Our goal is to develop novel small molecule antagonists of tau filament formation. Such molecules are expected to be useful therapeutic agents capable of halting the formation of a hallmark pathology common to Alzheimer's disease and other dementias. There are three specific Aims. First, using an established high-throughput screening method, small molecule antagonists of tau filament formation will be identified. Second, inhibitory activity will be confirmed using secondary screens. In addition, inhibitory activity will be demonstrated against all human tau isoforms found in the central nervous system. Third, the ability of lead inhibitors to disassemble existing filaments will be examined using both synthetic and authentic, Alzheimer's disease derived, tau filaments. Successful completion of these Phase I studies will lead to the identification of small molecules capable of arresting filament formation, regardless of tau isoform involved, in a manner that does not poison normal microtubule function. These experiments also will define appropriate candidates for Phase II studies, where biological activity and toxicity will be assessed.

Thesaurus Terms:
Alzheimer's disease, drug discovery /isolation, neuropharmacologic agent, tau protein high throughput technology, microtubule, neural degeneration, neurotoxicology, paired helical filament, psychopharmacology

NNI seeks to ameliorate neurodegeneration seen in Alzheimer's disease and other dementias. Toward this end, NNI scientists have targeted neurofibrillary tangle (NFT) formation for drug discovery. These lesions appear in concert with the onset of memory loss in AD, and are in fact the best markers for AD neurodegeneration known in the scientific literature. Thus NNI has pursued agents that interfere with NFT formation. As part of Phase I effort, the feasibility of inhibiting tau filament formation and driving filament depolymerization in vitro using small, drug-like ligands was demonstrated. Moreover, the ability of one such molecule to halt progression of neurodegeneration in an animal model of disease was shown. The goal of Phase II effort is to extend these results by validating tau fibrillization as a drug target, and proving that in vitro screening technology can successfully identify compounds that are active in animal models of tau-induced neurodegeneration. There are three Aims. First, NNI will expand its screening effort to identify additional classes of molecules with anti tau polymerization activity. NNI has shown the feasibility of using its screening technology to identify such molecules. Second, NNI will characterize the mechanism of action of its compounds, establishing a structure activity relationship for members of the existing structural family. Finally, NNI will examine the activity of active compounds in vivo, demonstrating entry into the brain, and determining a structure activity relationship for in vivo activity. At the end of the project, NNI will be in position to establish neuritic lesions (e.g., NFTs) as an authentic target for intensive preclinical development.

Thesaurus Terms:
Alzheimer's disease, brain disorder chemotherapy, drug discovery /isolation, neurofibrillary tangle, neuropharmacologic agent, tau protein disease /disorder model, drug screening /evaluation, neural degeneration, pharmacokinetics, polymerization, protein isoform, recombinant protein Agnatha, electron microscopy, immunocytochemistry, peptide library