Abstract
Fighting cancer is one of the major challenges of the 21st century. Among recently proposed treatments, molecular-targeted therapies are attracting particular attention. The potential targets of such therapies include a group of enzymes that possess the capability to catalyze at least two different reactions, so-called multifunctional enzymes. The features of such enzymes can be used to good advantage in the development of potent selective inhibitors. This review discusses the potential of multifunctional enzymes as anti-cancer drug targets along with the current status of research into four enzymes which by their inhibition have already demonstrated promising anti-cancer effects in vivo, in vitro, or both. These are PFK-2/FBPase-2 (involved in glucose homeostasis), ATIC (involved in purine biosynthesis), LTA4H (involved in the inflammation process) and Jmjd6 (involved in histone and non-histone posttranslational modifications). Currently, only LTA4H and PFK-2/FBPase-2 have inhibitors in active clinical development. However, there are several studies proposing potential inhibitors targeting these four enzymes that, when used alone or in association with other drugs, may provide new alternatives for preventing cancer cell growth and proliferation and increasing the life expectancy of patients.
Highlights
Cancer has become one of the greatest barriers to the increase of life expectancy in almost every country in the world, and is one of the biggest medical challenges of the21st century
We focus on four multifunctional enzymes that are abnormally expressed in different cancer cells, and that have been previously proposed as good drug targets for cancer treatment
Allows the cancer cells to maintain a high glycolytic flux. This is advantageous for the transformed cells because the maintenance a high glycolytic flux allows them to produce higher ATP rates when compared with oxidative phosphorylation, and provides them with intermediates that are vital for other important biosynthetic pathways
Summary
Cancer has become one of the greatest barriers to the increase of life expectancy in almost every country in the world, and is one of the biggest medical challenges of the. A panoply of proteins have been identified as potential targets, including some enzymes that belong to special class generally designated as “multifunctional enzymes”. These enzymes share a common characteristic: they possess the capability to catalyze at least two different reactions in the same or in different overlapping or distant active sites. We focus on four multifunctional enzymes that are abnormally expressed in different cancer cells, and that have been previously proposed as good drug targets for cancer treatment. We start this review with a global description of the biological role of each enzyme, followed by a description of its tertiary and quaternary structure; we provide evidence about its role in cancer development and/or survival; we describe the most promising inhibitors proposed to date targeting each enzyme
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