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Biotech / Medical : Indications -- Cancer -- Ignore unavailable to you. Want to Upgrade?

To: software salesperson who wrote (352)	4/3/2003 2:00:31 PM
From: tuck	Respond to of 1840

[tubacin: HDAC6-mediated -tubulin deacetylation] (say THAT 3 times fast) >>Published online before print April 3, 2003 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0430973100 Chemistry Cell Biology Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation Stephen J. Haggarty , Kathryn M. Koeller , Jason C. Wong , Christina M. Grozinger , and Stuart L. Schreiber ¶ Departments of *Molecular and Cellular Biology and Chemistry and Chemical Biology, Harvard Institute of Chemistry and Cell Biology, and Howard Hughes Medical Institute, Harvard University, 12 Oxford Street, Cambridge, MA 02138 Contributed by Stuart L. Schreiber, February 18, 2003 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 microtubule-associated 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.<< My understanding is that the HDAC inhibitors out there work on different isoforms (there are 8?), such as MOGN/Methylgene's MG98, which goes for HDAC1. Others . . . Aton's SAHA, VX-563, FK228, MS-275, CG-1521 & CG-1255, trichostatin A, valproic acid, sodium phenylbutyrate combo with ATRA. Cheers, Tuck