Methods for identifying and using IKK inhibitors

Details Methods for identifying and using IKK inhibitors Methods for identifying and using IKK inhibitors

2000-11-22

2003-11-18

Weddington, Kevin E. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S675000

Reexamination Certificate

active

06649654

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides methods and compositions for the identification and use of IKK inhibitors. In particular, the present invention provides cyclopentenone prostaglandins suitable for use as IKK inhibitors.
BACKGROUND OF THE INVENTION
The rapid and precise control of gene expression via transcription factors is critical to the survival of cells. Depending upon the inducing stimulus, it can be critical to the survival of a cell to have one or more genes rapidly induced, so that the resultant products are active. For example, an inflammatory response stimulated by an injury or infection, results in rapid vasodilation in the injured area and infiltration of effector cells such as macrophages. Vasodilation occurs within seconds or minutes of the response and is due, in part, to the expression of cytokines by cells in the injured region.
The rapid induction of the inflammatory and immune responses requires that the transcription factors involved in regulating such responses be present in the cell in a form that is amenable to rapid activation. Thus, upon exposure to an inducing stimulus, the response can quickly occur. If such transcription factors are not present in a cell in an inactive state, it is necessary to synthesize the factors upon exposure to an inducing stimulus, greatly reducing the speed with which a response can occur.
Regulation of transcription factor activities involved in such rapid gene induction can occur by various mechanisms. For example, in some cases, a transcription factor that exists in an inactive state in a cell can be activated by post-translational modification (e.g., phosphorylation of one or more serine, threonine, or tyrosine residues). Furthermore, the transcription factor can be rendered inactive by association of the factor with a regulatory factor, which, upon exposure to an inducing stimulus, is released from the transcription factor, thereby activating the transcription factor. Alternatively, an inactive transcription factor may have to associate with a second protein in order to produce transcriptional activity.
Rarely, as in the case of glucocorticoids, the inducing stimulus directly interacts with the inactive transcription factor, rendering it active and resulting in the induction of gene expression. However, more often, an inducing stimulus initiates the induced response by interacting with a specific receptor present on the cell membrane or by entering the cell and interacting with an intracellular protein. Furthermore, the signal generally is transmitted along a pathway, for example, from the cell membrane to the nucleus, due to a series of protein interactions. Such signal transduction pathways allow for the rapid transmission of extracellular inducing stimuli, such that appropriate gene expression is rapidly induced.
Although the existence of signal transduction pathways has long been recognized and many of the cellular factors involved in such pathways have been described, the pathways responsible for the expression of many critical responses, including the inflammatory and immune responses, have only been incompletely defined. For example, it is recognized that various inducing stimuli such as viruses and bacteria, activate common arms of the immune and inflammatory response. However, differences in the gene products expressed also are observed, indicating that these stimuli share certain signal transduction pathways, but also induce other pathways unique to the inducing stimulus. Furthermore, since inducing agents such as bacteria and viruses initially stimulate different signal transduction pathways, yet induce the expression of common genes, some signal transduction pathways must converge at a point such that the different pathways activate common transcription factors.
A clearer understanding of the proteins involved in such pathways facilitates descriptions of drug mechanisms of action. For example, such an understanding facilitates the determination of a drug's mechanism of action (e.g., in cases where the drug is known to interfere with gene expression regulated by a particular pathway, but the target of which is unknown). In addition, an understanding of the pathways involved facilitates the identification of defect(s) in the pathway(s) associated with diseases such as cancer. For example, the altered expression of cell adhesion molecules is associated with the ability of a cancer cell to metastasize. However, the critical proteins involved in the signal transduction pathway leading to expression of cell adhesion molecules have not been identified. Thus, there is a need in the art to identify the proteins involved in signal transduction pathways, particularly those proteins that result in the induction of gene products involved in the inflammatory and immune responses. Indeed, despite much research in the field, there remains a need in the art for compositions and methods for treating and/or preventing infectious as well as other diseases, and inflammation.
SUMMARY OF THE INVENTION
The present invention provides methods for identifying compounds with activities that inhibit IKK. In some preferred embodiments, the methods comprise contacting IKK, or a subunit or fragment of IKK with the compound. In some particularly preferred embodiments, the compound interacts with cysteine-179 of the IKK. In alternative embodiments, the method further comprises determining whether the compound interacts with cysteine-179, wherein the interaction with cysteine-179 correlates with activity as an IKK inhibitor.
The present invention also provides methods to prevent and/or treat diseases and/or conditions associated with NF&kgr;B. In particularly preferred embodiments, the method involves inhibition of the action of NF&kgr;B. The present invention further provides methods for the inhibition of IKK in vitro and in vivo, as well as methods to prevent NF&kgr;B activation in an animal. In some preferred embodiments, the animal is a mammal. In particularly preferred embodiments, the mammal is a human.
The present invention also provides methods to improve the therapeutic activity of COX2 inhibitors in animals (e.g., mammals, including but not limited to humans), comprising administering the COX2 inhibitor in combination with a compound that inhibits IKK activity to an animal. It is contemplated that COX2 inhibitors such as celecoxib, or Fecoxib, NS-398, and PD 98059 (Jones et al., Nat. Med., 18:1418-1423 [1999]), will find use with the present invention. The present invention further provides methods to inhibit the activity of IKK in a cell, comprising contacting the cell with a compound that interacts with IKK. In particularly preferred embodiments, the compound interacts with cysteine-179 of IKK.
The present invention further provides compounds, as well as pharmaceutical compositions comprising compounds that inhibit IKK. The present invention also provides pharmaceutical compositions comprising compounds that are COX2 inhibitors. In additional embodiments, the present invention provides pharmaceutical compositions comprising at least one compound that inhibits IKK, a COX2 inhibitor, and a pharmaceutically accepted carrier.
The present invention also provides the use of the compound of formula I, wherein R
1
and R
2
are each independently selected from hydrogen, (C
1
-C
12
)alkyl, and (C
2
-C
12
)alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more hydroxy, halo, nitro, trifluoromethyl, cyano, NRR, SR, or COOR; each R is independently selected from the group consisting of hydrogen and (C
1
-C
12
)alkyl; wherein the optional bond (i.e., the “ - - - ” bond) is present or absent, provided that when the optional bond is present, R
1
is not hydrogen; and n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.
The present invention further provides methods for the preparation of medicaments for inhibiting IKK and/or NF&kgr;B in an animal, and/or for improving the therapeutic activity of a COX2 inhibitor in an animal. In some preferred embodiments, the present i

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