Dysregulated metabolism is a feature of many diseases, including cancer. Here we report the development and application of reactivity-based methods to study the covalent signaling functions of cancer metabolites. Specifically, we have applied chemoproteomic methods to identify the covalent targets of metabolic acyl-CoAs as well as the oncometabolite fumarate. Mechanistic interrogation of these targets has been used to reveal new epigenetic mechanisms that may play a role in kidney cancer. In addition, we have developed a fluorogenic [3+2] cycloaddition that can be used to detect accumulation of the oncometabolite fumarate. Optimized probes allow direct detection of oncogenic mutations in the metabolic tumor supressor fumarate hydratase in cancer cell lines, as well as directly from kidney cancer patient tissue samples. These methods provide a fundamental demonstration into how chemical insights can be used to illuminate the signaling role of metabolites in cancer.

Harnessing intrinsic reactivity to understand covalent cancer metabolites

254th National Meeting (2017)

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