Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation

Abstract

Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, chemical genetic screen of 7,392 small molecules was used to discover ''tubacin,'' which inhibits ␣-tubulin deacetylation in mammalian cells. Tubacin does not affect the level of histone acetylation, gene-expression patterns, or cell-cycle progression. We provide evidence that class II histone deacetylase 6 (HDAC6) is the intracellular target of tubacin. Only one of the two catalytic domains of HDAC6 possesses tubulin deacetylase activity, and only this domain is bound by tubacin. Tubacin treatment did not affect the stability of microtubules but did decrease cell motility. HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules. Our results highlight the role of ␣-tubulin acetylation in mediating the localization of microtubuleassociated proteins. They also suggest that small molecules that selectively inhibit HDAC6-mediated ␣-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents.

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

“…We found potent synergy between R306465 and Bortezomib in a broad panel of haematological cell lines indicating that activity towards HDAC6 is not essential for Histone deacetylase inhibitors to work synergistically with Bortezomib. Histone deacetylase 6 also promotes migration and chemotactic movement in response to serum (Hubbert et al, 2002;Haggarty et al, 2003). These observations have led to the suggestion that HDAC6 may play a role in metastasis and angiogenesis.…”

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

“…Unfortunately, none of the numerous HDAC inhibitors is specific for single isoforms of HDAC, but few drugs show preferences for groups of HDACs or for single HDACs. FK228, for example, shows some preference for class I HDACs, and tubacin specifically targets HDAC-6 (27,28). Therefore, the challenge is to develop a new generation of HDAC inhibitors with improved specificity for certain HDAC isoforms and an increased efficacy compared with the pan-inhibitors such as TSA and suberoylanilide hydroxamic acid (SAHA) (29).…”

Histone deacetylase inhibitors: molecular mechanisms of action

“…Two novel synthetic compounds, SK7041 and SK7068, preferentially target HDAC1 and 2 and exhibit growth inhibitory effects in human cancer cell lines and tumor xenograft models (Kim et al, 2003a). A small molecule, tubacin, selectively inhibits HDAC6 activity and causes an accumulation of acetylated atubulin, but does not affect acetylation of histones, and does not inhibit cell cycle progression (Haggarty et al, 2003). No other HDACi for a specific HDAC has been reported.…”