Histone deacetylase 6 (HDAC6), an enzyme involved in protein degradation, exhibits several unique properties, such as cytoplasmic localization and ubiquitin binding. HDAC6 has emerged as an interesting therapeutic target in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Techniques enabling noninvasive HDAC6 imaging in the brain could enhance understanding of its pathologic role, but development of brain-penetrating radioligands for HDACs imaging by positron emission tomography (PET) remains challenging. Here, we report the synthesis and evaluation of an ¹⁸F-labeled tetrahydroquinoline derivative, [¹⁸F]2, based on the HDAC6 selective inhibitor SW-100 as a brain HDAC6 imaging radioligand. [¹⁸F]2 was synthesized via copper-mediated radiofluorination from an arylboronic precursor, followed by removal of the catalyst by solid-phase extraction and then hydroxamic acid formation. [¹⁸F]2 demonstrated good penetration and moderate stability in the mouse brain. In mouse plasma, however, [¹⁸F]2 was rapidly metabolized to a corresponding carboxylic acid form. Blocking studies in mice with unlabeled compound 2 and HDAC6 selective inhibitors, including tubastatin A and ACY-775, demonstrated that the HDAC6 inhibitors displaced over 80% of [¹⁸F]2 taken up in the brain, indicating selective binding of [¹⁸F]2. These results suggest that [¹⁸F]2 is a potentially useful PET radioligand for brain HDAC6 imaging.

01 Jun 2020·Experimental NeurologyQ2 · MEDICINE

HDAC6 inhibition promotes α-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice

Q2 · MEDICINE

Article

Author: Victor S.C. Wong ; Marion C. McKinnon ; Dianna E. Willis ; Nazia M. Alam ; David C. Goldberg ; Brett Langley ; Alan P. Kozikowski ; Michelle Swift ; Glen T. Prusky ; Sida Shen ; Christopher J. Costa ; Cristina Picci

Charcot-Marie-Tooth type 2A (CMT2A) peripheral neuropathy, the most common axonal form of CMT, is caused by dominantly inherited point mutations in the Mitofusin 2 (Mfn2) gene. It is characterized by progressive length-dependent degeneration of motor and sensory nerves with corresponding clinical features of motor and sensory impairment. There is no cure for CMT, and therapeutic approaches are limited to physical therapy, orthopedic devices, surgery, and analgesics. In this study we focus on histone deacetylase 6 (HDAC6) as a therapeutic target in a mouse model of mutant MFN2 (MFN2^R94Q)-induced CMT2A. We report that these mice display progressive motor and sensory dysfunction as well as a significant decrease in α-tubulin acetylation in distal segments of long peripheral nerves. Treatment with a new, highly selective HDAC6 inhibitor, SW-100, was able to restore α-tubulin acetylation and ameliorate motor and sensory dysfunction when given either prior to or after the onset of symptoms. To confirm HDAC6 is the target for ameliorating the CMT2A phenotype, we show that genetic deletion of Hdac6 in CMT2A mice prevents the development of motor and sensory dysfunction. Our findings suggest α-tubulin acetylation defects in distal parts of nerves as a pathogenic mechanism and HDAC6 as a therapeutic target for CMT2A.

20 Mar 2019·ACS Chemical NeuroscienceQ3 · MEDICINE

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome

Q3 · MEDICINE

Article

Author: Eubanks, James H. ; Benoy, Veronick ; Pardo, Marta ; Robers, Matthew B. ; Tavares, Maurício T. ; Van Den Bosch, Ludo ; Jope, Richard S. ; Bařinka, Cyril ; Zhang, Guiping ; Kozikowski, Alan P. ; Shen, Sida ; Szarics, Dora ; Zimprich, Chad A. ; Kutil, Zsófia

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1^-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC₅₀ = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1^-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1^-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.

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Indication	Highest Phase	Country/Location	Organization	Date
Fragile X Syndrome	Preclinical	US	StarWise Therapeutics LLC	14 Dec 2018

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