Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

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.

Keywords: cancer; molecular-targeted therapies; multifunctional enzymes.

Figure 3

Ribbon representation of the human PFK-2/FBPase-2 (PFKFB2) enzyme with the PDB ID 5HTK [26], obtained with VMD. The PFK-2 active site harbors an ATP and a citrate molecule (inside the Fru-6-P binding pocket) and the FBPase-2 active site harbors a frutose-6-phosphate molecule inside the F-2,6-P₂ binding pocket. All ligands are represented in licorice.

Figure 1

Schematic representation of the reaction catalyzed by the PFK-2 domain of the PFK-2/FBPase-2 enzyme.

Figure 2

Schematic representation of the reaction catalyzed by the FBPase-2 domain of the PFK-2/FBPase-2 enzyme.

Figure 4

Chemical structure of PFKFB3 (3PO, PFK15 and PFK158) and PFKFB4 (5MPN) inhibitors.

Figure 5

Schematic representation of the reaction catalyzed by the AICAR TFase domain of the ATIC enzyme.

Figure 6

Schematic representation of the reaction catalyzed by the IMPCHase domain of the ATIC enzyme.

Figure 7

Ribbon representation of the human ATIC enzyme with the PDB ID 1P4R [57] obtained with VMD. The AICAR TFase active site harbors the folate-based inhibitor BW1540U88UD, and the IMPCHase active site (of the ATIC monomer colored in yellow) harbors a xanthosine 5′->monophosphate molecule. All ligands are represented in licorice.

Figure 8

Chemical structure of AICAR TFase inhibitors.

Figure 9

Schematic representation of the reaction catalyzed by the epoxide hydrolase activity of the LTA₄H enzyme.

Figure 10

Schematic representation of the reaction catalyzed by the aminopeptidase activity of the LTA₄H enzyme.

Figure 11

Ribbon representation of the human LTA₄H enzyme with the PDB ID 3B7T [86] obtained with VMD. The LTA4H active site harbors a catalytic Zn²⁺ ion (colored in yellow) and an Arg-Ala-Arg substrate. All ligands are represented in licorice.

Figure 12

Chemical structure of one 5-LO inhibitor (Zileuton) and three LTA4H inhibitors (Acebilustat, LYS006 and RH00633).

Figure 13

Schematic representation of the reaction catalyzed by the lysine hydroxylase activity of the Jmjd6 enzyme.

Figure 14

Schematic representation of the reaction catalyzed by the arginine demethylation activity of the Jmjd6 enzyme.

Figure 15

Ribbon representation of the human Jmjd6 enzyme with the PDB ID 6MEV [137] obtained with VMD. The Jmjd6 active site harbors a catalytic Fe (II) ion (colored in yellow), one molecule of mono-Methyl Arginine and one molecule of 2-oxoglutaric acid. All ligands are represented in licorice.

Figure 16

Chemical structure of the JMJD6 inhibitors.