Hsp90 Inhibitor for Use in Treatment of Neurodegenerative Disease



MSK Investigators have discovered and developed small molecule inhibitors specifically targeting the Stress Chaperome through Stress Heat Shock Protein 90 (Stress Hsp90). Stress Hsp90 is part of the molecular chaperone protein complexes implicated in negative changes ongoing in brains afflicted by Alzheimer’s (AD), Parkinson’s, and other neurodegenerative diseases.

MSK’s lead compound, PU-AD, displays strong therapeutic efficacy as measured in survival, behavioral, biochemical, and immunohistochemical studies in AD mouse models. Results included amelioration of cognitive decline in AD, slowing of disease progression, and a delay to the terminal disease stage, extending the life-span of AD-afflicted mice equivalent to 8-12 years in humans.  MSK’s PU-AD technology platform includes development of an image-based diagnostic to identify AD patients who would benefit from PU-AD and other disease-modifying treatments years prior to the appearance of clinical symptoms.



The chaperome is a complex network of different molecular chaperones, such as Hsp90, and folding enzymes. It helps cells perform their normal housekeeping functions. But chronically overstressed cells contain, besides the ‘normal’ chaperome, a chaperome of distinct Hsp90 complexes, which are epigenetically, thermodynamically, and biochemically distinguishable from the ‘housekeeping’ complexes. These are referred to as Stress Hsp90. Their function is to facilitate the adverse proteome changes that occur in cells that are being chronically stressed, in this context, by the process of neurodegeneration.

AD patients have chaperomes which present both the housekeeping and the Stress Hsp90 complexes. PU-AD has the ability to act exclusively on Stress Hsp90 and not on the housekeeping chaperome. It can simultaneously affect multiple toxic proteins facilitated by Stress Hsp90 and associated with neurodegeneration. This provides a more comprehensive, multi-modal anti-neurodegenerative therapy than the mono-modal molecules that are the focus of most current drug discovery efforts.



  • PU-AD has shown excellent oral bioavailability and brain permeability
  • Non-toxic at active doses under acute and chronic systemic administration
  • Results in mouse models suggest the potential to treat AD at the different stages of the disease and extend lifespan
  • Co-development of an image-based diagnostic, PU-PET-AD, will allow the identification of AD patients who could benefit from the PU-AD drug or other disease-modifying therapies long before clinical symptoms appear



Current treatment approaches to AD focus on the manifestations of the disease, protein deposits called amyloid and tangles, rather than on its underlying cause. Toxic changes in the neuron develop years before deposits appear or the clinical AD symptoms develop. As such, therapies that attack the mechanisms behind the changes themselves are needed for a stronger impact on disease. That is why MSK’s PU-AD targets a facilitator of toxic changes in the neuron, the Stress Hsp90.

As a disease-modifying therapy or effective diagnostic, this platform technology could drastically change the AD landscape. Currently, AD is the only Top 10 cause of death that cannot be prevented, cure, or even slowed. In 2014, medical costs for the 36 million people living with AD totalled about $600 billion, a figure currently expected to double every 20 years.



Alzheimer’s and other neurodegenerative diseases



2 issued patents and 15 pending applications filed for chemical composition of matter and the AD diagnostic platform.



Dr. Gabriela Chiosis, Laboratory Head, and Associate Member, Chemical Biology, Sloan Kettering Institute, MSK



Imke Ehlers, PhD, CLP
Senior Licensing Manager
E-mail: ehlersi@mskcc.org

Stage of Development