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Tubacin

Tubacin is a highly potent and selective, reversible, cell-permeable HDAC6 inhibitor with an IC50 of 4 nM. The IC50 for other HDACs is 1000-fold higher, making tubacin both more selective and more potent than Tubastatin A, which also inhibits HDAC8. Tubacin inhibits alpha-tubulin deacetylation in mammalian cells. Unlike trichostatin A (TSA), which is a broad spectrum HDAC inhibitor, tubacin is specific for the tubulin deacetylase activity of HDAC6. Tubacin is a synthetic small molecule with chemical formula C41H43N3O7S and molecular weight: 721.86. It's chemical name is N1-(4-((2R,4R,6S)-4-(((4,5-diphenyloxazol-2-yl)thio)methyl)-6-(4-(hydroxymethyl)phenyl)-1,3-dioxan-2-yl)phenyl)-N8-hydroxyoctanediamide.  The total synthesis of tubacin was described by Hong et al [Letters in Organic Chemistry (2010), 7(1), 50-53].

Current developer:   Dana-Farber and The Broad Institute

Tubacin was originally discovered by scientists at the Broad Institute after performing a cell-based screen of a library of over 7000 small molecules. Tubacin is a highly potent, selective, reversible, cell-permeable HDAC6 inhibitor with an IC50 of 4 nM. The IC50 for other HDACs is 1000-fold higher, making tubacin both more selective and more potent than Tubastatin A.

According to Aldana-Masangkay et al's recent publication (Leuk Lymphoma. 2011 Aug;52(8):1544-55.)  tubacin showed a higher antiproliferative effect in acute lymphoblastic leukemia (ALL) cells than in normal hematopoietic cells. Treatment with tubacin led to the induction of apoptotic pathways in both pre-B and T cell ALL cells at a 50% inhibitory concentration (IC(50)) of low micromolar concentrations. Acetylation of α-tubulin increases within the first 30 min following treatment of ALL cells with tubacin. It was also observed an accumulation of polyubiquitinated proteins and poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the signaling pathways activated by tubacin appear to be distinct from those observed in multiple myeloma. The results suggest that targeting HDAC6 alone or in combination with chemotherapy could provide a novel approach to treat ALL.

1: Aldana-Masangkay GI, Rodriguez-Gonzalez A, Lin T, Ikeda AK, Hsieh YT, Kim YM,  Lomenick B, Okemoto K, Landaw EM, Wang D, Mazitschek R, Bradner JE, Sakamoto KM.  Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells. Leuk Lymphoma. 2011 Aug;52(8):1544-55. doi: 10.3109/10428194.2011.570821. Epub 2011 Jun 23. PubMed PMID: 21699378.

2: Kawada J, Zou P, Mazitschek R, Bradner JE, Cohen JI. Tubacin kills Epstein-Barr virus (EBV)-Burkitt lymphoma cells by inducing reactive oxygen species and EBV lymphoblastoid cells by inducing apoptosis. J Biol Chem. 2009 Jun 19;284(25):17102-9. doi: 10.1074/jbc.M809090200. Epub 2009 Apr 22. PubMed PMID: 19386607; PubMed Central PMCID: PMC2719348.