Identification of Aminothienopyridazine Inhibitors of Tau Assembly by Quantitative High-Throughput Screening

Center for Neurodegenerative Disease Research, Institute on Aging, and Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Biochemistry (Impact Factor: 3.01). 08/2009; 48(32):7732-45. DOI: 10.1021/bi9006435
Source: PubMed

ABSTRACT 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.

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Available from: Carlo Ballatore, Aug 14, 2015
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    • "How a change of MT stabilization or an enhancement of FAT might reduce the amount of hyperphosphorylated and misfolded tau in the PS19 mice is unclear, although a similar reduction of tau pathology was observed after intranasal administration of the pleiotropic peptidic MT-stabilizing agent, NAP (Matsuoka et al., 2007; Matsuoka et al., 2008). We have examined whether EpoD has a direct effect on tau fibrillization, using a well-characterized in vitro assay (Crowe et al., 2009), and find that the compound has essentially no effect on tau assembly (data not shown). Although it is impossible to definitively exclude the possibility of off-target effects of EpoD that might lead to increased degradation of misfolded tau, it is interesting to note that kinesin-1 deficient mice develop dystrophic axons with increased amounts of hyperphosphorylated tau (Falzone et al., 2009). "
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    • "Agents capable of reducing abnormal phosphorylation and self-assembly of tau offer attractive strategies for the prevention and/or treatment of tau-mediated neurodegenerative disorders (Brunden et al., 2009, 2010). Currently, different studies have identified several inhibitors of fibrillogenesis in vitro using a variety of tau assembly assays (Brunden et al., 2009; Bulic et al., 2010; Chirita et al., 2004; Crowe et al., 2009; Li et al., 2009; Taniguchi et al., 2005; Wischik et al., 1996). With the exception of methylene blue, which has already progressed to human clinical trials, none of these compounds have been assessed for efficacy in vivo. "
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