Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system

  • Nat Commun. 2021 Aug 3;12(1):4669. doi: 10.1038/s41467-021-24821-2.
Alexander Bolaender   #  1 ,  Danuta Zatorska   #  1 ,  Huazhong He   #  1 ,  Suhasini Joshi   #  1 ,  Sahil Sharma   #  1 ,  Chander S Digwal   #  1 ,  Hardik J Patel  1 ,  Weilin Sun  1 ,  Brandon S Imber  1 ,  Stefan O Ochiana  1 ,  Maulik R Patel  1 ,  Liza Shrestha  1 ,  Smit K Shah  1 ,  Shuo Wang  1 ,  Rashad Karimov  1 ,  Hui Tao  1 ,  Pallav D Patel  1 ,  Ananda Rodilla Martin  1 ,  Pengrong Yan  1 ,  Palak Panchal  1 ,  Justina Almodovar  1 ,  Adriana Corben  2 ,  Andreas Rimner  3 ,  Stephen D Ginsberg  4  5 ,  Serge Lyashchenko  6 ,  Eva Burnazi  6 ,  Anson Ku  7 ,  Teja Kalidindi  7 ,  Sang Gyu Lee  7 ,  Milan Grkovski  8 ,  Bradley J Beattie  8 ,  Pat Zanzonico  8 ,  Jason S Lewis  6  7 ,  Steve Larson  7 ,  Anna Rodina  1 ,  Nagavarakishore Pillarsetty  7 ,  Viviane Tabar  9 ,  Mark P Dunphy  7 ,  Tony Taldone  1 ,  Fumiko Shimizu  10  11 ,  Gabriela Chiosis  12  13
Affiliations
  • 1. Program in Chemical Biology, Sloan Kettering Institute, New York, NY, USA.
  • 2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4. Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA.
  • 5. Departments of Psychiatry, Neuroscience & Physiology and the NYU Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA.
  • 6. Radiochemistry and Molecular Imaging Probes Core, Sloan Kettering Institute, New York, NY, USA.
  • 7. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10. Program in Chemical Biology, Sloan Kettering Institute, New York, NY, USA. [email protected].
  • 11. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • 12. Program in Chemical Biology, Sloan Kettering Institute, New York, NY, USA. [email protected].
  • 13. Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 34344873 DOI: 10.1038/s41467-021-24821-2
Abstract

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as Cancer and Alzheimer's Disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.

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