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Identification of Novel Small Molecules as Tau Protein Aggregation Inhibitors…

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2011 / SBIR
Agency Tracking Number:
R43AG039129
Solicitation Year:
2011
Solicitation Topic Code:
NIA
Solicitation Number:
PA10-050
Small Business Information
PROTEOTECH, INC.
12040 115TH AVE N.E. KIRKLAND, WA 98034-
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2011
Title: Identification of Novel Small Molecules as Tau Protein Aggregation Inhibitors for
Agency: HHS
Contract: 1R43AG039129-01A1
Award Amount: $770,675.00
 

Abstract:

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by brain amyloid plaques consisting of insoluble beta-amyloid (A2) and tau protein containing neurofibrillary tangles (NFTs). AD drug discovery strategies have been largelyfocused on reducing brain A2 levels, with substantially less emphasis on tau-directed approaches. In the past decade, ProteoTech Inc has developed a number of different in vitro screening technologies and cellular models that identified new and potent inhibitors of amyloidosis. The techniques led us to design and synthesize a class of [new chemical entities consisting of small molecules (200-400 MW) containing bis-catechols,] some of them found to be potent inhibitors of protein/peptide aggregates that areof central importance for AD, Parkinson disease and systemic AA amyloidosis. Preliminary results for this Phase I project demonstrated that some of our new chemical entities have abilities to disrupt/inhibit tau protein fibril formation in vitro and in relevant innovative cell-based assays. [We hypothesize that certain small compounds in our unique small molecule new chemical entity library can serve as direct inhibitors of tau aggregation/fibrillogenesis, and may have great potential as new therapeutic agents for AD and other tauopathies.] The major objective our proposal is to identify specific small molecule compounds from ProteoTech's unique library for their ability to inhibit/disrupt tau aggregation/fibrillogenesis using both in vitro and cell-based assays. In [Specific Aim 1 we will screen a group of ~50 small molecule compounds (all representing new chemical entities) developed at ProteoTech (small molecules containing polyhydroxylated aromatic compounds) for their ability to inhibit tau protein fibril formation and to disrupt pre-formed tau fibrils using in vitro assays including Thioflavin T fluorometry, SDS-PAGE/western blot analysis and quantitation, CD spectroscopy, and electron microscopy.] In Specific Aim 2 we will utilize cell lines that inducibly express tau repeat domains (TauRD) to screen/validate our lead compounds identified in aim 1 for their ability to affect intracellular tau multimerization/ aggregation using Western analysis for soluble/insoluble TauRD aggregates, and Thioflavin S staining and electron microscopy for TauRD aggregates/fibrils. We will also test whether these compounds can rescue TauRD-induced microtubule network disruption and cytotoxicity as determined by immunostaining and quantitative image analysis. The most active compounds identified in this project will lead to a future Phase II SBIR project for optimizing these key lead compounds for drugability, brain penetration, pharmacokinetics and non-toxicity, and for testing their efficacy in relevant transgenic animal models that mimic many of the hallmarks of tau protein aggregation as observed in NFTs in AD and related tauopathies. PUBLIC HEALTH RELEVANCE: This Phase I SBIR project will lead to the development of novel small molecule drugs for the treatment oftau protein aggregation found in the neurofibrillary tangles of Alzheimer disease. Neurofibrillary tangle formation is one of the pathological hallmarks of Alzheimer's disease, the leading cause of dementia in the elderly.

Principal Investigator:

Alan D. Snow
425-823-6364
snow@proteotech.com

Business Contact:

Alan D. Snow
425-823-6364
snow@proteotech.com
Small Business Information at Submission:

PROTEOTECH, INC.
12040 115TH AVE N.E. KIRKLAND, WA 98034-

EIN/Tax ID: 191174373
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No