Tubacin - a specific small molecule inhibitor of HDAC6 tubulin deacetylase activity
HDAC 6 inhibitor and Niltubacin, an inactive derivative of tubacin
The aggresome pathway prevents accumulation of misfolded proteins. If such proteins fail to fold correctly and are not degraded by the proteasome, they can form aggregates in cells. These aggregates are transported via the microtubules using the dynein/dynactin motor complex. Histone deacetylase 6 (HDAC6) is a class II HDAC protein that deacetylates alpha-tubulin and associates with dynein to facilitate transport of aggresomes through the cytosol to the proteasome for degradation.
Innovations and Advantages
Stuart Schreiber’s laboratory at the Broad Institute isolated a small molecule inhibitor of HDAC6 in a chemical genetic screen of 7392 small molecules and cell-based assay. This inhibitor, known as 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 inhibits HDAC6 and causes increased acetylation of ?-tubulin, accumulation of polyubiquitinated proteins, and apoptosis. Tubacin does not affect global histone deacetylation, gene-expression profiling, or cell cycle progression
The effects of tubacin have been studied in cell-based cancer models including hematologic malignancies, such as multiple myeloma and leukemia, and also solid tumor models, such as pancreatic cancer and ovarian cancer. Tubacin in combination with the proteasome inhibitor bortezomib (Velcade) resulted in increased ?-tubulin acetylation and accumulation of polyubiquitinated proteins in multiple myeloma cells. Tubacin was also found to inhibit interaction of HDAC6 with dynein and augmented activation of c-Jun NH2-terminal kinase and caspase-3, -8 and -9. Both bortezomib and tubacin together induced synergistic antitumor activity in multiple myeloma cells and primary bone marrow plasma cells.
Useful as a tool in many research areas such as cancer, apoptosis, HDAC activity, aggresome and ubiquitin pathways, etc., tubacin is available for non-exclusive license in research-use.
Niltubacin, an inactive derivative of tubacin, can be used as a negative control compound and is also available for non-exclusive license in research-use.
Intellectual Property Status: Issued U.S. patent nos.: 8,304,451; other patent(s) pending
Chemical Structure of Tubacin
Issued and pending patent applications.
Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. 2003. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A. 100(8):4389-94.
Haggarty SJ, Koeller KM, Wong JC, Butcher RA, Schreiber SL. 2003. Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays. Chem Biol. 10(5):383-96.
Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC. 2005. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 102(24):8567-72.
Saji S, Kawakami M, Hayashi S, Yoshida N, Hirose M, Horiguchi S, Itoh A, Funata N, Schreiber SL, Yoshida M, Toi M. 2005. Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene. 24(28):4531-9.
Wong JC, Hong R, Schreiber SL. 2003. Structural biasing elements for in-cell histone deacetylase paralog selectivity. J Am Chem Soc. 125(19):5586-7.
Anderson, Kenneth C.
Greenberg, Edward F.
Haggarty, Stephen J.
Kwiatkowski, Nicholas Paul
Schreiber, Stuart L.
Shaw, Jared T.
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Vivian Berlin, Director of Business Development
Reference Harvard Case #2436