Fructose metabolism may play an important role in the initiation and development of cancer. Certain types of cancer overexpress Glut 5, the highly selective fructose transporter, to increase fructose uptake. The de novo synthesis of fructose from glucose via polyol pathway is also upregulated. Recently, Christofk’s group and others discovered that Ketohexokinase (KHK), an enzyme that catalyzes the conversion of fructose to fructose-1-phospate, is upregulated in several cancers and is critical for cancer cell proliferation both in vitro and in vivo. Additionally, KHK is a safe target for pharmacological inhibition for cancer treatment, because humans born with KHK deficiency are asymptomatic. Since KHK is important for cancer growth but not for normal tissues, it is considered a highly desirable target for cancer treatment. Efforts in medicinal chemistry and biology are being taken to develop novel KHK inhibitors. Through collaboration with Prof. Daniel Nomura at UC Berkeley, four small molecules that bind with KHK via covalent bond formation have been developed via chemoproteomics-enabled covalent ligand discovery. Additionally, a high throughput screen of 200,000 small molecule library will be conducted soon to discover novel molecules to inhibit KHK activity. Finally, starting with one existing KHK inhibitor, more than twenty analogues have been synthesized in order to improve the original compound’s potency and pharmacokinetic property. Two KHK activity assays, the CellTiter-Glo and pyruvate kinase/lactate dehydrogenase-coupled assay, have been developed to test KHK activity with small molecule inhibition. In conclusion, KHK is a promising target for cancer treatment and more effort is required to develop novel inhibitors. The novel KHK inhibitors we develop will be useful to further study the role of KHK in cancer development and may result in an anticancer drug targeting cancer metabolism.

Targeting cancer fructose metabolism: Development of novel ketohexokinase inhibitors

2019 Fall National Meeting

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