Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes

Abstract

Disclosed are methods for the treatment of proliferative disorders using compounds and/or environmental conditions which result in a difference in sensitivity of targeted and non-targeted cells. Certain of the methods involve the identification and use of allele-specific inhibitors of conditionally essential genes.

Description

BACKGROUND[0001] This invention is concerned with the field of treatment of proliferative disorders, including malignant and nonmalignant proliferative diseases.[0002] The following information is provided to assist the understanding of the reader, none of that information is admitted to be prior art to the present invention.[0003] The treatment of cancer is one of the most heavily investigated areas in biomedical research today. Although many anticancer drugs have been and continue to be discovered, there remains the immense problem of developing drugs that will be specifically toxic to cancer cells without killing normal cells and causing toxic, often permanent, damage to vital organs or even death. One common measure of the clinical usefulness of any anticancer drugs is its therapeutic index: the ratio of the median lethal dose (LD.sub.50) to the median effective dose (ED.sub.50) of the drug. With some cancer therapeutics this ratio is in the range of 2-4, indicating a high risk ...

AI Technical Summary

Benefits of technology

0050] The term "less active" indicates that the inhibitor will inhibit growth of or kill a cell containing only the allelic form of a gene on which the inhibitor is more active at concentrations at which it does not significantly inhibit the growth of or kill a cell containing only an allelic form on which the inhibitor is less active.

0051] The term "drug" or "inhibitor" refers to a compound or molecule which, when brought into contact with a gene, its RNA transcript, or its gene product which the compound inhibits, reduces the rate of a cellular process, reduces the level of a cellular constituent, or reduces the level of activity of a cellular component or process. This description is meant to be illustrative of the understanding of the meaning of the term to those skilled in the art and not limiting. Thus, the term generally indicates that a compound has an inhibitory effect on a cell or process, as understood by those skilled in the art. Examples of inhibitory effects are a reduction in expression of a gene product, reduction in the rate of catalytic activity of an enzyme, and reduction in the rate of formation or the amount of an essential cellular component. The blocking or reduction need not be complete, in most cases, for the inhibitor to have useful activity. Thus, in the present invention, "inhibitors" are targeted to genes, their RNA transcript, or their protein product that are essential for cell viability or proliferation. Such inhibitors would have the effect of inhibiting essential functions, leading to loss of cell viability or inhibition of cell proliferation. In preferred embodiments, such inhibitors cause cell death or stop cell proliferation. In preferred embodiments of this invention, inhibitors specifically include a molecule or compound capable of inhibiting one or more, but not all, alleles of genes, their RNA transcript, or their protein product that are essential for cell survival or proliferation. The terms "inhibitor of a gene" or "inhibitor of an allele" as used herein include inhibitors acting on the level of the gene, its gene product, its RNA transcript, its protein product, or modifications thereof and is explicitly not limited to those inhibitors or drugs that work on the gene sequence itself.

Problems solved by technology

Although many anticancer drugs have been and continue to be discovered, there remains the immense problem of developing drugs that will be specifically toxic to cancer cells without killing normal cells and causing toxic, often permanent, damage to vital organs or even death.

With some cancer therapeutics this ratio is in the range of 2-4, indicating a high risk of toxic side effects to the patient.

Indeed, most anticancer drugs are associated with a high incidence of adverse drug events.

The poor therapeutic index of most anticancer drugs not only limit the clinical efficacy of these drugs for the treatment of cancer, but limits their usefulness for treating many non-malignant, proliferative disorders.

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