Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening
| Autor: | Anne-Marie L. Hogan, Douglas S. Auld, Donna M. Huryn, James Inglese, Kurt R. Brunden, Jennifer Wichterman, Alex Crowe, John Q. Trojanowski, Christopher P. Austin, Wenwei Huang, Carlo Ballatore, Virginia M.-Y. Lee, Amos B. Smith, Ruili Huang, Ronald L. Johnson, Joshua G. McCoy |
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| Rok vydání: | 2009 |
| Předmět: |
Protein Conformation
High-throughput screening Tau protein tau Proteins Fibril Bioinformatics Biochemistry Article chemistry.chemical_compound Protein structure mental disorders Drug Discovery Animals Humans Senile plaques biology Molecular Structure Drug discovery Chemistry Small molecule Pyridazines Tauopathies biology.protein Thioflavin Protein Multimerization |
| Zdroj: | Biochemistry. 48(32) |
| ISSN: | 1520-4995 |
| Popis: | Inclusions comprised of fibrils of the microtubule- (MT-) associated protein tau are found in the brains of those with Alzheimer's disease (AD) and other neurodegenerative tauopathies. The pathology that is observed in these diseases is believed to result from the formation of toxic tau oligomers or fibrils and/or from the loss of normal tau function due to its sequestration into insoluble deposits. Hence, small molecules that prevent tau oligomerization and/or fibrillization might have therapeutic value. Indeed, examples of such compounds have been published, but nearly all have properties that render them unsuitable as drug candidates. For these reasons, we conducted quantitative high-throughput screening (qHTS) of approximately 292000 compounds to identify drug-like inhibitors of tau assembly. The fibrillization of a truncated tau fragment that contains four MT-binding domains was monitored in an assay that employed complementary thioflavin T fluorescence and fluorescence polarization methods. Previously described classes of inhibitors as well as new scaffolds were identified, including novel aminothienopyridazines (ATPZs). A number of ATPZ analogues were synthesized, and structure-activity relationships were defined. Further characterization of representative ATPZ compounds showed they do not interfere with tau-mediated MT assembly, and they are significantly more effective at preventing the fibrillization of tau than the Abeta(1-42) peptide which forms AD senile plaques. Thus, the ATPZ molecules described here represent a novel class of tau assembly inhibitors that merit further development for testing in animal models of AD-like tau pathology. |
| Databáze: | OpenAIRE |
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