Modular Synthesis of Cell-Permeating 2-Ketoglutarate Esters: Chemical Tools for Oncometabolite Antagonism and Detection

Authors

• TT Zengeya
• RA Kulkarni
• JL Meier

Abstract

2-ketoglutarate (2-KG) plays a central role in cellular homeostasis, functioning both as a central metabolite and a cofactor for Fe(II)-dependent dioxygenase enzymes. Cancers driven by the production of “oncometabolites” such as succinate, fumarate, and 2-hydroxyglutarate disrupt the dioxygenase cofactor function of 2-KG, promoting the stabilization of oncogenic transcription factors and epigenetic silencing of tumor suppressor genes. Chemical methods capable of restoring 2-KG cofactor activity in living cells thus represent a vital goal. One strategy that has been explored to reactivate 2-KG utilizing enzymes in oncometabolite-driven cancers is to pharmacologically raise the intracellular 2-KG concentration using cell-permeable 2-KG esters. Cell-permeable 2-KG esters are known to manifest a variety of interesting phenotypic effects, including the disruption of hypoxic gene expression, extension of C. elegans lifespan, and maintenance of stem cell pluripotency. However, the challenging synthesis of these compounds has limited such applications, as well as the development of structure-function data for this compound class. Here we report a concise synthetic route providing access to regioisomerically pure 2-KG esters in 2-3 steps. This approach enabled the first quantitative benchmarking of how structure influences the ability of 2-KG esters to induce degradation of the oncogenic transcription factor HIF-1α, and may facilitate novel therapeutic and diagnostic approaches.

Scientific Focus Area: Chemical Biology

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