Discovery of Threonine Tyrosine Kinase (TTK) Degraders Utilizing an Electrophilic Monomethyl Fumarate Handle

Abstract

Threonine tyrosine kinase (TTK), a core component of the spindle assembly checkpoint, plays an essential role in mitosis, and its inhibition has emerged as a promising therapeutic strategy for human cancers. We previously reported multiple approaches to target TTK, including reversible inhibitors, covalent inhibitors, and PROTAC degraders. In this study, we advance these efforts by developing a novel monovalent degrader of TTK. The representative compound, 26, generated by appending an electrophilic monomethyl fumarate handle to a TTK inhibitor, effectively induced TTK degradation and demonstrated superior antiproliferative activity across diverse cancer cell lines. Mechanistic investigations suggested that compound 26 primarily engages RNF126 and stabilizes its association with TTK, thereby inducing TTK ubiquitination and subsequent proteasomal degradation. Collectively, this work provides the first example of a TTK molecular glue-like degrader and introduces a new electrophilic handle for the rational design of degraders with reduced nonspecific cytotoxicity.