The present invention relates to the identification, isolation, sequencing and characterization of a new member of the histone deacetylase family, as well as its transcripts, gene products, associated sequence information, and related genes. The present invention also relates to methods for detecting and diagnosing carriers of normal and mutant alleles of these genes, methods for detecting and diagnosing diseases, methods of identifying genes and proteins related to or interacting with such genes and proteins, methods of screening for potential therapeutics for diseases, methods of treatment for diseases, and to cell lines and animal models useful in screening for and evaluating potentially useful therapies for diseases. In a particular aspect of the present invention, a novel family member, HDAC7, is described and its interaction with SMRT/N-CoR and mSin3A, its biochemical properties and subcellular localization are characterized. In addition, evidence is provided that the HDAC4, 5, and 7 deacetylases may mediate nuclear receptor repression. The findings described here indicate that two or more classes of histone deacetylases can collectively contribute to SMRT/N-CoR action and that at least some deacetylases may directly associate with SMRT/N-CoR in a mSin3A independent fashion.
The present invention features substantially pure HDAC9, HDAC9a, HDAC9(.DELTA.NLS), HDAC9a(.DELTA.NLS), an HDRP(.DELTA.NLS) polypeptides, and isolated nucleic acid molecules encoding those polypeptides. The present invention also features vectors containing HDAC9, HDAC9a, HDAC9(.DELTA.NLS), HDAC9a(.DELTA.NLS), and HDRP(.DELTA.NLS) nucleic acid sequences, and cells containing those vectors.
Histone deacetylase inhibitors and uses thereof are provided that have the general formula ##STR00001## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted straight chained C.sub.1-12 alkyl, C.sub.2-12 aminoalkyl or C.sub.2-12 oxaalkyl, and a substituted and unsubstituted 3, 4, 5, 6, 7 or 8 membered ring, with the proviso that R.sub.3 and R.sub.4 are not both hydrogen; R.sub.5 is selected from the group consisting of a carbonyl, a substituted or unsubstituted C.sub.1-3 alkyl, a substituted or unsubstituted --C.sub.1-3 alkyl-C(O), a substituted or unsubstituted --C(O)--C.sub.1-3 alkyl, and a substituted or unsubstituted --C(O)C(O)C.sub.1-3 alkyl; M is a substituent capable of complexing with a protein metal ion; and L is a substituent comprising a chain of 3 12 atoms connecting the M substituent to the carbon atom alpha to the L substituent.
Compounds that may be used to inhibit histone deacetylase having the formula Z-Q-L-M or Z-L-M wherein M is a substituent capable of complexing with a deacetylase catalytic site and/or a metal ion; L is a substituent providing between 0 10 atoms separation between the M substituent and the remainder of the compound; and Z and Q are as defined herein.
Histone deacetylase inhibitors and uses thereof are provided that have the general formula ##STR00001## whereinR.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted straight chained C.sub.1-12 alkyl, C.sub.2-12 aminoalkyl or C.sub.2-12 oxaalkyl, and a substituted and unsubstituted 3, 4, 5, 6, 7 or 8 membered ring, with the proviso that R.sub.3 and R.sub.4 are not both hydrogen;R.sub.5 is selected from the group consisting of a carbonyl, a substituted or unsubstituted C.sub.1-3 alkyl, a substituted or unsubstituted --C.sub.1-3 alkyl-C(O), a substituted or unsubstituted --C(O)--C.sub.1-3 alkyl, and a substituted or unsubstituted --C(O)C(O)C.sub.1-3 alkyl;M is a substituent capable of complexing with a protein metal ion; andL is a substituent comprising a chain of 3-12 atoms connecting the M substituent to the carbon atom alpha to the L substituent.
Compounds that may be used to inhibit histone deacetylase having the formula Z-Q-L-M or Z-L-M wherein M is a substituent capable of complexing with a deacetylase catalytic site and/or a metal ion; L is a substituent providing between 0-10 atoms separation between the M substituent and the remainder of the compound; and Z and Q are as defined herein.
