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Review
. 2022 Jan 4;132(1):e148550.
doi: 10.1172/JCI148550.

Clinical development of metabolic inhibitors for oncology

Kathryn M Lemberg  1   2 , Sadakatali S Gori  1   3 , Takashi Tsukamoto  1   3   4 , Rana Rais  1   3   4 , Barbara S Slusher  1   2   3   4   5   6
Affiliations
Review

Clinical development of metabolic inhibitors for oncology

Kathryn M Lemberg et al. J Clin Invest. .

Abstract

Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

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Conflict of interest statement

Conflict of interest: RR and BSS are inventors on Johns Hopkins University patents covering novel glutamine antagonist prodrugs: “Prodrugs of glutamine analogs” (WO2017023774A1); “Methods and compositions for treating metabolic reprogramming disorders” (WO2017023787A1); “Novel glutamine antagonists and uses thereof” (WO2019071110A1). These patents have been licensed to Dracen Pharmaceuticals Inc. RR and BSS are founders of and hold equity in Dracen Pharmaceuticals Inc. BSS also serves as a scientific consultant to Dracen. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Figures

Figure 1
Figure 1. Metabolic inhibitors under clinical investigation for oncology applications.
Schematic depicts the metabolic pathways and processes inhibited by agents described in this Review. Agents are shown in red text. Key enzymes are shown in pink. Pathways are labeled in yellow. Metabolites are shown in blue.
Figure 2
Figure 2. Structures of metabolic inhibitors currently under clinical investigation, grouped by target pathway.
Structures of KHK2455, HTI-1090, and sirpiglenastat have not yet been disclosed.
See this image and copyright information in PMC

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