Flavopiridol methods and compositions for HIV therapy

Details Flavopiridol methods and compositions for HIV therapy Flavopiridol methods and compositions for HIV therapy

2001-02-15

2003-12-09

Padmanabhan, Sreeni (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06660750

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of kinase inhibitors, transcription and virology. More particularly, it concerns the surprising discovery that flavopiridol dramatically inhibits the transcription elongation factor, P-TEFb. As P-TEFb is essential for HIV productive infection, the present invention provides new, effective methods, compositions and kits for treating HIV infections and AIDS using flavopiridol and combinations thereof.
2. Description of Related Art
The Human Immunodeficiency Virus (HIV) is a retrovirus that productively infects human and primate cells. In humans, infection with HIV is life-threatening and leads to AIDS, the terminal syndrome due to HIV infection. Although HIV has been the subject of intense biomedical and clinical research, there are still few effective therapies for use against HIV infection and AIDS. In certain areas of the world, HIV is particularly prevalent; for example, in Africa, one out of every four adults reportedly carries the HIV virus. HIV infection, and the resultant AIDS syndrome, are thus unfortunately widespread and continue to exert a significant toll in human suffering and economic terms.
There are about 15 therapeutics currently approved for administration to patients with HIV. Most of these are either protease inhibitors, such as Saquinavir, the first protease inhibitor approved for treatment of HIV (under the name, Invirase™); or nucleoside reverse transcriptase inhibitors, including AZT (marketed as Retrovir™). Unfortunately, the effectiveness of even the most potent and specific drugs, those that inhibit a required HIV protease, is limited as resistant strains arise quickly. In fact, treatment with current drugs has been reported to stimulate the selection and propagation of resistant viral strains. It has therefore been suggested that the most effective treatments are those incorporating a combinatorial use of different drugs. However, these treatments can lead to dose-limiting toxicity and significant side-effects, limiting their application.
Therefore, there remains in the art an evident need for new and more effective anti-HIV agents. Within this general desire, the identification of drugs other than protease inhibitors and nucleoside reverse transcriptase and drugs that target other important process in the HIV life cycle are needed. The identification of a drug that acts against a cellular target would be an important advance in the field, particularly as such a drug would make it difficult for resistant strains to arise.
SUMMARY OF THE INVENTION
The present invention addresses the foregoing long-felt need and other deficiencies in the art by identifying new and effective strategies for treating viral infections, particularly HIV infections and AIDS. The invention is based, in part, upon the discovery that the compound flavopiridol, used in clinical trials for the treatment of cancer, dramatically inhibits the transcription elongation factor, P-TEFb. As P-TEFb is required for HIV propagation and replication in human cells, flavopiridol compounds can now be used to inhibit cellular P-TEFb, thus interfering with HIV replication and providing new treatments for HIV infections and AIDS.
The invention thus provides new methods, compositions, kits and uses for treating HIV infections and AIDS using flavopiridol compounds and, optionally, combinations of such compounds with other HIV therapeutics. One particularly surprising aspect of this invention is the fact that the cellular targets for flavopiridol action were thought to have been identified, leaving no motivation to search for other candidate molecules to which flavopiridol may bind or inhibit.
A further unexpected benefit of the invention is the ability of flavopiridol to inhibit P-TEFb, and consequent HIV infection, at extremely low concentrations. This allows flavopiridol compounds to be used in HIV treatment at concentrations that are much lower than those employed to produce an anti-tumor effect, thus providing HIV and AIDS treatments with reduced or absent side-effects and toxicities. In fact, the effectiveness of flavopiridol in inhibiting P-TEFb and HIV infection is such that the present invention provides pharmaceutical compositions comprising surprisingly low, but nonetheless therapeutically effective, levels of flavopiridol.
The invention thus provides a variety of flavopiridol-based compositions and methods for inhibiting the enzyme complex P-TEFb (positive transcription elongation factor b). As used herein, unless otherwise stated or evident from scientific usage, the term “P-TEFb” is employed to mean a functional, operative enzyme complex with biological activity. In structural terms, the P-TEFb enzyme complex is comprised of a cyclin-dependent kinase subunit (Cdk9) and a larger, cyclin subunit (cyclin T1). Again, unless otherwise stated or scientifically evident, the “P-TEFb” of the present disclosure comprises both the kinase (Cdk9) and cyclin (cyclin T1) subunits.
According to the convention in the art, as used herein, unless otherwise stated or made evident, the term “HIV” is often used succinctly to refer to “HIV-1”. Those of ordinary skill in the art will understand that where “HIV-2” is particularly intended, this will be recited. In the absence of such direction, “HIV” may include “HIV-1 and HIV-2”, with “HIV-1” being particularly preferred for treatment by the invention.
Currently, the most preferred flavopiridol-like compound is flavopiridol itself. Flavopiridol is 4H-1-Benzopyran-4-one,2-(2-chlorophenyl)-5,7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, hydrochloride, (−)-cis-; which may also be termed (−)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8-[4R(3 S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one, hydrochloride.
However, those of ordinary skill in the art will understand that the present invention is by no means limited to the use of flavopiridol itself, but encompasses a range of “flavopiridol-like compounds”, such as analogs and derivatives. Exemplary flavopiridol compounds other than the parent flavopiridol compound include 2-thio and 2-oxo flavopiridol analogs. Any flavopiridol-based compound may be used in the invention so long as it inhibits P-TEFb in at least substantially the same manner as flavopiridol itself. Given the mechanistic studies provided herein, flavopiridol compounds that inhibit P-TEFb to a greater extent, and/or with other advantageous properties, can now be designed and used in the present invention.
Irrespective of the source of the flavopiridol-based compounds, the invention particularly contemplates the use of one, two, three or four distinct flavopiridol analogues or derivatives, up to and including a plurality of such compounds. This exemplifies the use of singular terminology throughout the entire application, wherein the terms “a” and “an” are used in the sense that they mean “at least one”, “at least a first”, “one or more” or “a plurality” of the referenced components or steps, except in instances wherein an upper limit is thereafter specifically stated or would be understood by one of ordinary skill in the art. The operable limits and parameters of combinations, as with the amounts of any single agent, will be known to those of ordinary skill in the art in light of the present disclosure.
By the term “inhibiting”, it is meant that practice of the present invention results in the “inhibition” of P-TEFb, preferably the inhibition of one or more of the “biological activities” of P-TEFb. Most preferably, the inhibition takes the form of ultimately inhibiting the role of P-TEFb in transcription.
Although by no means bound by the following mechanism, the present inventors believe that the invention functions due to the inhibition of the cyclin-dependent kinase (cdk9) subunit of P-TEFb. Once inhibited, the cdk9 kinase subunit is unable to effectively phosphorylate RNA polymerase II, thus inhibiting transcription. However, any form of “inhibition” of P-TEFb is encompassed by the present invention. As advantageous

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