UCLA researchers in the Department of Chemistry and Biochemistry have synthesized novel KHK inhibitors that can result in anticancer drugs targeting cancer metabolism.
BACKGROUND: Fructose is a naturally occurring sugar found in fruits and vegetables, and is an integral part of the human diet. In comparison to its functional isomer, glucose, which can be metabolized by almost every human cell type, fructose is mainly metabolized by liver cells. Here, ingested fructose is mainly metabolized by ketohexokinase (KHK). In this process, KHK phosphorylates fructose to fructose-1-phosphate (F1P), which is then hydrolyzed to dihydroxyacetone phosphate (DHAP) and glyceraldehyde (GA), and where GLUT 5 is the fructose specific transporter. There is both experimental and clinical evidence that links an increased fructose intake with the growth, proliferation and survival of cancer cells. Specifically, certain cancer cells overexpress GLUT 5. Additionally, the de novo synthesis of fructose from glucose via polyol pathway is also upregulated. Interestingly, UCLA researchers led by Dr. Heather Christofk, have shown that KHK is upregulated in several cancers and is critical for cancer proliferation.
INNOVATION: UCLA researchers led by Dr. Michael Jung and Dr. Heather Christofk have developed novel KHK inhibitors. As KHK is a desirable cancer target and is a safe target for pharmacological inhibition of cancer treatment, UCLA researchers have invented four small molecules that can bind KHK with high affinity. These inhibitors have been developed with chemoproteomics covalent bond discovery. Additionally, 20 analogues of a known KHK inhibitor have been synthesized to improve its potency and pharmacokinetic properties.
POTENTIAL APPLICATIONS:
- Target cancers linked to fructose metabolism
- Improve KHK inhibition
- Inhibit or decrease cancer cell proliferation
ADVANTAGES:
- Increases pharmacological properties of known KHK inhibitors.
- Multiple KHK inhibitors have been developed for a pharmacologically safe target.
- KHK inhibition has been clinically tested in patients with NAFLD and T2D (https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14946) but not yet for patients with cancer.
DEVELOPMENT-TO-DATE: KHK inhibitors have been validated by two activity assays.
KEYWORDS: cancer, cancer metabolism, small molecules, metabolism