Preclinical Evaluation of a Novel Hsp90 inhibitor in Mutant Tau Mice

DESCRIPTION (provided by applicant): Hereditary mutations within the MAPT (microtubule-associated protein tau) gene result in the pathologic and intra-neuronal aggregation of the tau protein that leads to frontotemporal dementia (FTD). The development of therapeutics for misfolded and abnormally processed (i.e. hyper-phosphorylated) tau species is necessary for sufferers of these autosomal tauopathic disorders and other neurological disorders which present with abnormal tau accumulation such as Alzheimer's disease (AD) and Parkinson's disease (PD). Molecular chaperones that are induced following a heat shock stimulus direct either the refolding of misfolded proteins and/or their targeting to the proteasome for degradation. Heat shock protein 90 (HSP90) inhibitors such as geldanamycin (GA) and its derivatives (17-allylamino-17-demethoxygeldanamycin;17-AAG) can pharmacologically modulate chaperone levels and have recently been implicated for the treatment of cancer;sponsor NCI, Phase II) and mouse models of neurodegenerative disorders. In fact, Waza and colleagues recently showed that systemic administration of 17-AAG can markedly ameliorate motor impairments and life span in the spinal and bulbar muscular atrophy transgenic mouse model without detectable toxicity, by reducing amounts of monomeric and aggregated mutant androgen receptor. This study illustrates that Hsp90 inhibitors can be administrated chronically (20 weeks) and is well-tolerated. After screening a small panel of novel HSP90 inhibitors in a novel In-Cell Western assay that allows for direct intracellular quantitation of native and aberrant tau protein species, we identified a potent, blood brain barrier permeable HSP90 inhibitor (EC102) that significantly reduces abnormal tau species in vitro. In addition, we found that affected regions from human AD brain tissue have a significantly lower nanomolar binding affinity of Hsp90 for this novel inhibitor similar to tumor cells, while micromolar affinity was demonstrated in unaffected regions, comparable to normal cells. This suggests for the first time that in neurons, which progressively accumulate abnormal proteins in neurodegenerative disorders, and in this case AD, Hsp90 becomes engaged in active chaperoning and stabilization of these proteins and the Hsp90 adopts a novel high-affinity state. Thus these studies provide compelling evidence for the use of Hsp90 inhibitors to enhance Hsp90-mediated phospho-tau degradation in AD. We therefore propose that treatment with this compound may delay the progression of pathology and restore memory loss in mice that express a mutant form of human tau (P301L) driven by the tetracycline operator (rTg4510).