p53 Inhibitors and therapeutic use of the same

Abstract

The therapeutic use of temporary p53 inhibitors in the treatment of p53-mediated diseases, conditions, and injuries is disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of provisional application Ser. No. 60 / 117,881, filed Jan. 29, 1999.FIELD OF THE INVENTION [0002] The present invention relates to temporary p53 inhibitors and their use in therapy, for example, in cancer treatment, in modifying tissue response to a stress, and in modifying cell aging. More particularly, the present invention relates to compounds having the ability to effectively and temporarily inhibit p53 activity, and that can be used therapeutically, alone or in conjunction with a therapy, like chemotherapy or radiation therapy during cancer treatment, to treat a disease or condition where temporary inhibition of p53 activity provides a benefit. Examples of compounds that temporarily inhibit p53 activity and can be used therapeutically have the following general structural formulae (I) through (IV): [0003] and pharmaceutically acceptable salts and hydrates thereof. BACKGROUND OF THE INVENTION [00...

AI Technical Summary

Benefits of technology

"The present invention relates to the use of temporary p53 inhibitors for therapeutic purposes. These inhibitors can reversibly inhibit p53 activity and can be used to treat various diseases and conditions associated with p53 activity, such as cancer, trauma, and aging. The invention also provides pharmaceutical compositions and methods for using temporary p53 inhibitors in combination with other therapeutic agents for improved cancer treatment. The temporary p53 inhibitors can also be used to protect normal cells from damage caused by radiation or other stresses. Overall, the invention provides new tools for the treatment and prevention of p53-related diseases and conditions."

Problems solved by technology

For example, it has been observed that p53-deficient mice almost universally contract cancer because such mice lack a gene capable of maintaining genomic stability (L. A. Donehower et al., Nature, 356, p.

Specifically, radiation therapy and chemotherapy exhibit severe side effects, such as severe damage to the lymphoid and hematopoietic system and intestinal epithelia, which limit the effectiveness of these therapies.

Inactivation of p53 has been considered an undesirable and unwanted event, and considerable effort has been expended to facilitate cancer treatment by restoring p53 function.

However, p53 restoration or imitation causes the above-described problems with respect to damaging normal tissue cells during chemotherapy or radiation therapy.

These normal cells are subjected to stress during cancer therapy, which leads the p53 in the cell to cause a programmed death.

This accumulation can affect proliferating cells and lead to a gradual decrease in overall proliferative capacity of tissues associated with age.

However, there are several important objectives that should be satisfied before a therapy involving suppression of p53 is implemented, for example: (i) providing a p53 inhibitor that is sufficiently efficacious in vivo for practical administration as a therapeutic drug (i.e., inhibits p53 activity in a micromolar (μm) range of concentrations); (ii) providing a p53 inhibitor that has a sufficiently low toxicity for use in therapy, and also does not cause undesirable side effects at concentrations sufficient to inhibit p53 activity; (iii) exhibiting a p53 inhibition that is reversible because long-term p53 inactivation can significantly increase the risk of cancer; (iv) during temporary p53 inhibition, the cells should recover from the applied stress and the p53-activating signal should be eliminated or reduced, otherwise restoration of p53 activity while the p53-activating signal is active could result in cell damage; and (v) the p53 suppression therapy is not associated with a dramatic increase in the frequency of cancer development, i.e., the therapeutic inhibitors target p53-mediated control of cellular response to stress, but do not affect p53-mediated control of oncogene transformation.

Prior investigators did not consider therapeutic p53 inhibitors because therapeutic p53 suppression was considered a disadvantage leading to the onset and proliferation of cancerous tumors.

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