title: Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules.
abstract: Three scaffolds with inhibitory activity against the heat shock protein 70 (Hsp70) family of chaperones have been found to enhance the degradation of the microtubule associated protein tau in cells, neurons, and brain tissue. This is important because tau accumulation is linked to neurodegenerative diseases including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Here, we expanded upon this study to investigate the anti-tau efficacy of additional scaffolds with Hsp70 inhibitory activity. Five of the nine scaffolds tested lowered tau levels, with the rhodacyanine and phenothiazine scaffolds exhibiting the highest potency as previously described. Because phenothiazines also inhibit tau aggregation in vitro, we suspected that this activity might be a more accurate predictor of tau lowering. Interestingly, the rhodacyanines did inhibit in vitro tau aggregation to a similar degree as phenothiazines, correlating well with tau-lowering efficacy in cells and ex vivo slices. Moreover, other Hsp70 inhibitor scaffolds with weaker tau-lowering activity in cells inhibited tau aggregation in vitro, albeit at lower potencies. When we tested six well-characterized tau aggregation inhibitors, we determined that this mechanism of action was not a better predictor of tau-lowering than Hsp70 inhibition. Instead, we found that compounds possessing both activities were the most effective at promoting tau clearance. Moreover, cytotoxicity and PAINS activity are critical factors that can lead to false-positive lead identification. Strategies designed around these principles will likely yield more efficacious tau-lowering compounds.
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.
authors.forename: Mackenzie D
authors.initials: MD
authors.lastname: Martin
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Baker
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.
authors.forename: Amirthaa
authors.initials: A
authors.lastname: Suntharalingam
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Nordhues
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Shelton
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.
authors.forename: Dali
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Sabbagh
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine , Durham, North Carolina 27710, United States.
authors.forename: Timothy A J
authors.initials: TA
authors.lastname: Haystead
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.affiliation: Department of Molecular Medicine and Alzheimer's Institute, University of South Florida , Tampa, Florida 33613, United States.|James A. Haley Veteran's Hospital , 13000 Bruce B. Downs Blvd. Tampa, Florida 33612, United States.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D054852:Small Molecule Libraries / Q000494:pharmacology*; D016875:tau Proteins / Q000037:antagonists & inhibitors*
chemical_list: D018840:HSP70 Heat-Shock Proteins; C054369:MAPT protein, human; D054852:Small Molecule Libraries; D016875:tau Proteins