A member of a new class of drugs called epichaperome inhibitors, PU-AD is an oral, brain-permeable inhibitor of the molecular chaperone heat shock protein 90. HSP90 stabilizes mutant or aberrantly modified proteins associated with cancer and multiple neurodegenerative diseases.
HSP90 inhibitors enhance degradation of pathogenic proteins and promote cell survival in animal models of tau pathology, and of Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis/frontotemporal dementia, Huntington’s disease, and spinal and bulbar muscular atrophy (reviewed in Carman et al., 2013). Brain-penetrant HSP90 inhibitors were reported to enhance the degradation of mutated or hyperphosphorylated tau in mouse models (May 2007 news). Another brain-penetrant inhibitor enhanced working memory and spatial learning/memory in Tg2576 AD mice, and improved conditioned fear memory after infusion of Aβ into the brain (Wang et al., 2016).
Although all cells express HSP90 at high levels, PU-AD and some other HSP90 inhibitors bind with high affinity to HSP90 from cancer cells and AD tissue, but not from normal tissue, suggesting the possibility of selective inhibition in disease states (Moulick et al., 2011; Dickey et al., 2007).
Affinity purification using PU-AD, and proteomic analyses, have identified HSP90-centered, stable chaperone complexes that emerge in cells under stress, including in cancer, Parkinson’s, and Alzheimer’s diseases (Rodina et al., 2016; Kishinevsky et al., 2018; Joshi et al., 2018). In AD tissues and mouse models, these complexes, dubbed epichaperomes, incorporate cell proteins not normally associated with HSP90, including some involved in synaptic function, learning, and memory. PU-AD treatment dissociates the epichaperome, and restores HSP90’s normal protein associations (Inda et al., 2020).
PU-AD has been tested in the PS19 tau mouse and the 3xTg mouse. After 6 to 12 weeks of thrice-weekly dosing, 3-month-old or 8- to 9-month-old PS19 mice performed better on learning and memory trials in a Barnes maze, compared to untreated animals (Inda et al., 2020). Treatment also normalized deficits in synaptic long-term potentiation, extended life span, and decreased phospho-tau and tau oligomers in multiple brain regions. PU-AD had similar effects on tau and on memory and learning in 3XTg mice.
Between June and December 2019, Samus Therapeutics ran a Phase 1 study of PU-AD in 40 healthy volunteers, who receive single or multiple doses of an oral solution of drug or placebo. At the CTAD 2019 conference, the company reported that single doses of 10, 20, or 30 mg were well-tolerated, with mild adverse events and linear pharmacokinetics. Healthy elderly volunteers completed one week of 20 mg per day doses, with no events resulting in interruption of dosing (see Dec 2019 press release).
A second Phase 1 study, at Memorial Sloan Kettering Cancer Center, New York, evaluated a radioactively labelled form of PU-AD (1241-PU-AD) as a diagnostic reagent in people with cancer and/or AD. This trial enrolled five participants who received a low dose of 1241-PU-AD, followed by PET-CT. It was completed in June 2019. The investigators reported low binding of the PET ligand in the brain of a cognitively normal 58-year-old, but elevated retention in a 71-year-old person with AD (Inda et al., 2020). Results in cancer patients were also published (Pillarsetty et al., 2019).
Samus is testing another epichaperome inhibitor, PU-H71, in Phase 1 for multiple forms of cancer. For details, see clinicaltrials.gov.
For details on PU-AD trials, see clinicaltrials.gov.
Last Updated: 29 Jan 2020
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