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  3. Development and Pharmacochemical Characterization Discover a Novel Brain-Permeable HDAC11-Selective Inhibitor with Therapeutic Potential by Regulating Neuroinflammation in Mice

Development and Pharmacochemical Characterization Discover a Novel Brain-Permeable HDAC11-Selective Inhibitor with Therapeutic Potential by Regulating Neuroinflammation in Mice

  • J Med Chem. 2023 Nov 16. doi: 10.1021/acs.jmedchem.3c01491.
Ping Bai 1 2 3 4 5,  Yan Liu 6,  Liuyue Yang 7,  Weihua Ding 7,  Prasenjit Mondal 8,  Na Sang 1 2 3 4 5,  Gang Liu 9,  Xiaoxia Lu 9,  Thanh Tu Ho 10,  Yanting Zhou 1 2 3 4 5,  Rui Wu 1 2 3 4 5,  Vishal C Birar 6,  Moses Q Wilks 11,  Rudolph E Tanzi 8,  Hening Lin 10 12,  Can Zhang 8,  Weimin Li 1 2 3 4 5,  Shiqian Shen 7,  Changning Wang 6
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 4 The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan 610041, China.
  • 5 State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Chengdu, Sichuan 610041, China.
  • 6 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • 7 Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • 8 Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.
  • 9 Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, People's Republic of China.
  • 10 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
  • 11 Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • 12 Howard Hughes Medical Institute; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
PMID: 37972387 DOI: 10.1021/acs.jmedchem.3c01491
Abstract

Recent studies have shown that the epigenetic protein histone deacetylase 11 (HDAC11) is highly expressed in the brain and critically modulates neuroimmune functions, making it a potential therapeutic target for neurological disorders. Herein, we report the development of PB94, which is a novel HDAC11 Inhibitor. PB94 exhibited potency and selectivity against HDAC11 with IC50 = 108 nM and >40-fold selectivity over other HDAC isoforms. Pharmacokinetic/pharmacodynamic evaluation indicated that PB94 possesses promising drug-like properties. Additionally, PB94 was radiolabeled with carbon-11 as [11C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for drug development in live Animals. Furthermore, we demonstrated that neuropathic pain was associated with brain upregulation of HDAC11 and that pharmacological inhibition of HDAC11 by PB94 ameliorated neuropathic pain in a mouse model. Collectively, our findings support further development of PB94 as a selective HDAC11 Inhibitor for neurological indications, including pain.

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