Fumarate-tagged TTK inhibitor turns into a monovalent degrader via RNF126
- Appending an electrophilic monomethyl fumarate handle to a TTK inhibitor gave a single-warhead degrader, with no E3 ligand attached.
- The lead compound drove TTK degradation and showed stronger antiproliferative activity than the parent inhibitor across several cancer cell lines.
- Mechanistic work points to the E3 ligase RNF126, which the compound stabilizes in complex with TTK, leading to ubiquitination and proteasomal turnover.
💡 Points
Monovalent degraders are attractive because you keep the molecular weight and permeability of a plain inhibitor. The catch is that a fumarate handle is a cysteine-reactive group, so I'd want proteome-wide reactivity data before believing RNF126 is the whole story. Still, if the handle transfers across kinase scaffolds, it's a cheap trick to try on any inhibitor series you already own.