Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors

Epigenetic
modifiers of the histone deacetylase (HDAC) family contribute
to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration.
Hence, histone deacetylase inhibitors (HDACi), which alter protein
acetylation, gene expression patterns, and cell fate decisions, represent
promising new drugs for the therapy of these diseases. Whereas pan-HDACi
inhibit all 11 Zn2+-dependent histone deacetylases (HDACs)
and cause a broad spectrum of side effects, specific inhibitors of
histone deacetylase 6 (HDAC6i) are supposed to have less side effects.
We present the synthesis and biological evaluation of Marbostats,
novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline
derivatives. Our lead compound Marbostat-100 is a more potent and
more selective HDAC6i than previously established well-characterized
compounds in vitro as well as in cells. Moreover,
Marbostat-100 is well tolerated by mice and effective against collagen
type II induced arthritis. Thus, Marbostat-100 represents a most selective
known HDAC6i and the possibility for clinical evaluation of a HDAC
isoform-specific drug.