Metabolic Rewiring in Cancer: Small Molecule Inhibitors in Colorectal Cancer Therapy

Abstract

Alterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment.

Keywords: Warburg effect; cancer; colorectal cancer; glutaminolysis; lactate dehydrogenase; lipid metabolism; metabolism.

Figure 1

Schematic representation of “Warburg effect” in cancer cells.

Figure 2

Reaction catalyzed by LDH.

Figure 3

Chemical structures of lactate dehydrogenase inhibitors 1–13.

Figure 4

De novo fatty acid synthesis pathway functions in cancer cells.

Figure 5

FASN-catalyzed reaction.

Figure 6

Chemical structures of compounds 14–17 as fatty acid synthase inhibitors.

Figure 7

ACLy-catalyzed reaction.

Figure 8

Chemical structures of compounds 18 and 19 as ATP-citrate lyase inhibitors.

Figure 9

ACCA-catalyzed reaction.

Figure 10

Chemical structure of compound 20 as acetyl-CoA carboxylase-α inhibitor.

Figure 11

GLS and GDH catalyzed reactions.

Figure 12

Glutamine metabolic pathways in cancer cells.

Figure 13

Chemical structures of compounds 21–26 as glutaminolysis inhibitors.

Figure 14

Chemical structures of inhibitors 27–29.