Development of Glucose Transporter (GLUT) Inhibitors.

Elena S Reckzeh,Herbert Waldmann

doi:10.1002/ejoc.201901353

Abstract

The discovery of novel compound classes endowed with biological activity is at the heart of chemical biology and medicinal chemistry research. This enables novel biological insights and inspires new approaches to the treatment of diseases. Cancer cells frequently exhibit altered glycolysis and glucose metabolism and an increased glucose demand. Thus, targeting glucose uptake and metabolism may open up novel opportunities for the discovery of compounds that differentiate between normal and malignant cells. This review discusses the different chemical approaches to the development of novel inhibitors of glucose uptake through facilitative glucose transporters (GLUTs), and focusses on the most advanced and potent inhibitor classes known to date. GLUT inhibitors may find application not only in the treatment of cancer, but also of other proliferative diseases that exhibit glucose addiction.

Highlights

IntroductionHave inspired numerous concepts for the identification of bioactive compounds, including Biology-oriented synthesis (BIOS)[2] or the design and synthesis of pseudo-natural products (for a discussion of the different NP-based approaches see ref[3])
Bioactive small molecules are the cornerstones of medicinal chemistry and chemical biology research and continue to define a large fraction of most recently approved drugs, e.g. the PI3K inhibitor Piqray (Alpelisib) for the combinatorial treatment of breast cancer.[1]
Addressing the first rate-limiting step, i.e. glucose uptake, may, be a viable opportunity to initiate new medicinal chemistry programs aimed at the treatment of cancer and other diseases, which are characterized by hyperproliferation

Summary

Introduction

Have inspired numerous concepts for the identification of bioactive compounds, including Biology-oriented synthesis (BIOS)[2] or the design and synthesis of pseudo-natural products (for a discussion of the different NP-based approaches see ref[3]). Since glycolysis fuels biosynthetic pathways and thereby drives cell proliferation, interfering with glycolysis offers a promising strategy to restrict the energy and substrate supply for biosynthesis and cell proliferation.[7] Addressing the first rate-limiting step, i.e. glucose uptake, may, be a viable opportunity to initiate new medicinal chemistry programs aimed at the treatment of cancer and other diseases, which are characterized by hyperproliferation (for more details see Reckzeh et al.[8]) For glucose uptake, both normal cells and cancer cells employ facilitative transmembrane transporters termed GLUTs. Here we summarize the discovery of the currently most potent and advanced (IC50 < 1 μM) GLUT inhibitors (for an overview of more GLUT inhibitors regardless of their potency please refer to Granchi et al.[9]). Both NP-derived and NP-inspired as well as non-NP based inhibitors are discussed

Discovery of Novel GLUT Inhibitors

Natural Product GLUT Inhibitors

Natural Product-Inspired GLUT Inhibitors

Non-Natural GLUT Inhibitors

Findings

Summary and Outlook