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Updated: Aug 26, 2025
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Conditional Covalent Lethality Driven by Oncometabolite Accumulation
Minervo Perez1, Kellie D Nance1, Daniel W Bak2
1Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21072, United States.
Abstract:
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome driven by mutation of the tumor suppressor fumarate hydratase (FH). Inactivation of FH causes accumulation of the electrophilic oncometabolite fumarate. In the absence of methods for reactivation, tumor suppressors can be targeted via identification of synthetic lethal interactions using genetic screens. Inspired by recent advances in chemoproteomic target identification, here, we test the hypothesis that the electrophilicity of the HLRCC metabolome may produce unique susceptibilities to covalent small molecules, a phenomenon we term conditional covalent lethality. Screening a panel of chemically diverse electrophiles, we identified a covalent ligand, MP-1, that exhibits FH-dependent cytotoxicity. Synthesis and structure-activity profiling identified key molecular determinants underlying the molecule's effects. Chemoproteomic profiling of cysteine reactivity together with clickable probes validated the ability of MP-1 to engage an array of functional cysteines, including one lying in the Zn-finger domain of the tRNA methyltransferase enzyme TRMT1. TRMT1 overexpression rescues tRNA methylation from inhibition by MP-1 and partially attenuates the covalent ligand's cytotoxicity. Our studies highlight the potential for covalent metabolites and small molecules to synergistically produce novel synthetic lethal interactions and raise the possibility of applying phenotypic screening with chemoproteomic target identification to identify new functional oncometabolite targets.
Insights
Researchers discovered a new way to target cancer by exploiting the unique metabolic vulnerabilities in Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). A novel covalent molecule, MP-1, selectively kills cancer cells with fumarate hydratase (FH) mutations.
Area of Science:
- Biochemistry
- Oncology
- Chemical Biology
Background:
- Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome caused by mutations in the fumarate hydratase (FH) tumor suppressor gene.
- FH inactivation leads to the accumulation of the electrophilic oncometabolite fumarate, creating unique metabolic vulnerabilities.
- Targeting tumor suppressors often involves identifying synthetic lethal interactions, especially when direct reactivation is not feasible.
Purpose of the Study:
- To investigate whether the electrophilic nature of the HLRCC metabolome creates susceptibility to covalent small molecules, termed conditional covalent lethality.
- To identify novel therapeutic strategies for HLRCC by screening for FH-dependent cytotoxicity.
- To explore the potential of chemoproteomic methods for identifying functional oncometabolite targets.
Main Methods:
- Screening a diverse panel of electrophilic small molecules to identify compounds with FH-dependent cytotoxicity.
- Synthesizing and performing structure-activity relationship (SAR) profiling of identified covalent ligands.
- Utilizing chemoproteomic profiling with clickable probes to identify protein targets and cysteine reactivity.
- Assessing the role of identified targets, such as TRMT1, in mediating the compound's effects.
Main Results:
- A covalent ligand, MP-1, was identified that exhibits significant FH-dependent cytotoxicity.
- SAR studies elucidated key molecular features responsible for MP-1's activity.
- Chemoproteomic analysis confirmed MP-1 engages multiple functional cysteines, including one in the tRNA methyltransferase TRMT1.
- TRMT1 overexpression partially rescued tRNA methylation and attenuated MP-1's cytotoxicity, implicating TRMT1 as a key target.
Conclusions:
- The study demonstrates the potential of exploiting metabolic vulnerabilities with covalent small molecules for targeted cancer therapy in HLRCC.
- Conditional covalent lethality represents a promising strategy for developing novel cancer therapeutics.
- Phenotypic screening combined with chemoproteomic target identification can uncover new functional oncometabolite targets and therapeutic avenues.
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