Conditional Covalent Lethality Driven by Oncometabolite Accumulation

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.