Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1997-11-10
2004-03-16
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06706762
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the modulation of nuclear receptor mediated processes, compounds useful therefor and methods for the identification and use of such compounds.
BACKGROUND OF THE INVENTION
The actions of steroids, retinoids and thyroid hormones are mediated by intracellular nuclear receptors whose coordinate activity defines the physiological response (Mangelsdorf and Evans,
Cell
83:841-850 (1995)). These receptors are all structurally related and constitute a superfamily of nuclear regulatory proteins that modulate gene expression in a ligand-dependent fashion. Previous studies have demonstrated that the 9-cis retinoic acid receptor (RXR) serves as a common heterodimeric partner for thyroid hormone receptor (TR), retinoic acid receptor (RAR), vitamin D receptor (VDR), prostanoids (PPAR), as well as numerous orphan receptors (Kliewer et al. (1992)
Nature
355:446-449).
Transcriptional repression is an intrinsic part of endocrine physiology and contributes to feedback regulation associated with the inhibition of the physiologic response. Indeed, the thyroid hormone receptor is converted to an oncogene by mutations which block hormone binding and create a constitutive transcriptional repressor (Damm et al.
EMBO J
. 6:375-382 (1987),
Nature
3:593-597 (1989); Graf and Beug
Cell
34:7-9 (1983); Sap et al.
Nature
340:242-244 (1989)). Multiple studies on transcriptional silencing by verbA and the non-liganded thyroid hormone receptor suggest that repression is required for oncogenesis and that this process is mediated by a diffusible co-factor(s) that associates with the ligand binding domain (LBD) (Baniahmad et al.
Mol. Cell. Biol
. 15:76-86 (1995); Casanova et al.
Mol. Cell. Biol
. 14:1756-1765 (1994)).
Transcriptional co-repressors (SMRT and N-CoR) have recently been identified that associate with non-liganded receptors resulting in suppression of basal transcriptional activity (see, for example, Chen and Evans
Nature
377:454-457 (1995); Chen et al.
PNAS
93:7567-7571 (1996); Horlein et al.
Nature
377:397-404 (1995); and Sande and Privalsky
Mol. Endo
. 10:813-825 (1996)).
While the mechanism of this repression is not known, chromatin remodeling has been suggested to be a component of transcriptional regulation (for review see Wolffe and Pruss.
Curr. Biol
. 6:234-237 (1996): Felsenfeld
Cell
86:13-19 (1996)). Indeed, it has been suggested that specific transcriptional activation may be involved in local changes in chromatin structure. In fact, it has recently been demonstrated that nuclear hormone receptors may utilize the CREB binding protein (CBP) or its homolog p300 (Janknecht and Hunter
Nature
383:22-23 (1996)), to function as a nuclear receptor co-factor (Chakravarti, et al.
Nature
383:99-103 (1996); Hanstein et al.
PNAS
93:11540-11545 (1996); Kamei et al.
Cell
85:403-414 (1996); Yao et al.
PNAS
93:10626-10631 (1996)). In addition to CBP/p300, multiple hormone-dependent and independent associated co-factors have been characterized (Fondell et al.
PNAS
93:8392-8333 (1996)).
Of particular interest is the recent demonstration that CPB/p300 associates with the histone acetylase P/CAF (Yang X-J et al.
Nature
382:319-324 (1996)) which displays significant sequence homology to the yeast transcription activator GCN5, also known to be a histone acetylase (Brownell et al.
Cell
84:843-851 (1996)). Further, CBP/p300 harbors intrinsic histone acetyltransferase activity, resulting in alternative or perhaps simultaneous histone acetylation (Ogryzko et al.
Cell
87:953-959 (1996)). The notion that multiple transcriptional co-activators possess acetylase activity suggests that their recruitment to a DNA template would locally destabilize nucleosomes, creating a permissive state for promoter activation.
The symptoms of certain neoplastic diseases have been ameliorated by the administration of retinoids. However, some patients afflicted with acute promyelocytic leukemia (APL) respond poorly (if at all), to retinoid differentiation therapy, while others enter disease remission following high doses of retinoic acid treatment. Although APL cell lines have been identified as being retinoid sensitive, there has been no evidence to explain the distinct retinoid responses in APL patients.
Accordingly, there is a need in the art for a further understanding of the interaction(s) between the various components involved in regulation of hormone mediated processes. A clearer understanding of these processes will facilitate the development of methods to modulate hormone mediated processes, as well as assays for the identification of compounds useful for such modulation. Moreover, there is a need in the art for novel approaches for treating human cancer. These and other needs in the art are addressed by the present invention.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have discovered that histone deacetylase associates with hormone receptor complexes and contributes to the repression thereof. We have further discovered that exposure of a repressed system to histone deacetylase inhibitors relieves this repression. Thus, histone deacetylase inhibitors have been found to be useful for the activation of genes responsive to hormone receptors.
In accordance with another aspect of the invention, formulations useful for modulation of hormone-mediated processes have been developed. In addition, assays have been developed for the identification of compounds useful to modulate the above-described processes. In accordance with another aspect, methods of employing such compounds to modulate or enhance hormone mediated processes, such as human cancers.
In accordance with the present invention, SMRT and components of the histone deacetylase complex have been discovered to function as effectors of cellular transformation. Specifically, the interaction of SMRT with PLZF-RAR&agr; and PML-RAR&agr; has been discoved to play a critical role in the pathogenesis of acute promyelocytic leukemia (APL). These findings provide the first direct link between nuclear receptor cofactors and human cancer by providing evidence that a transcriptional corepressor may directly contribute to human cancers. Moreover, pharmacological manipulation of the association/dissociation of nuclear receptor cofactors will prove to be beneficial as it provides novel approaches to treatment of human diseases.
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Taunton et al. “A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p,” Science (Apr. 1996) 272:408-411.*
Chen et al. “Retinoic acid is required for and potentiates differentiation of Acute Promyelocytic Leukemia cells by nonretinoid agents,” Blood (1994) 84(7): 2122-29, Oct. 1994.*
Chen and Evans, “A transcriptional co-repressor that interacts with nuclear hormone receptors”Nature377:454-457 (1995).
Hörlein, et al., “Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor”Nature377:397-404 (1995).
Tallman, M.S., “Differentiating therapy with all-trans retinoic acid in acute myeloid leukemia”Leikemia10 (Suppl. 1):S12-S15 (1996).
Agura, et al., “Identification and Sequence Analysis of the Promoter for the Leukocyte Integrin &bgr;-Subunit (CD18): A Retinoic Acid-Inducible Gene”Blood79 (3):602-609 (1992).
Albagli, et al., “The BTB/POZ Domain: A New Protein-Protein Interaction Motif Common to DNA-and Actin-binding Proteins1”Cell Growth & Differentiation6:1193-1198 (1995).
Alland, et al., “Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression”Nature387:49-55 (1997).
Ayer, et al., “Mad-Max Transcriptional Repression Is Mediated by Ternary Complex Formation with Mammalian Homologs of Yeast Repressor Sin3”Cell80:767-776 (1995).
Baniahmad, et al., “Modular Structure of a Chicken Lyso
Evans Ronald M.
Lin Richard J.
Nagy Laszlo
The Salk Institute for Biological Studies
Witz Jean C.
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