The protein kinase TTK (Mps1) plays a critical role in the mitotic checkpoint. Inhibition of TTK causes chromosome missegregation, resulting in apoptosis. NTRC has developed a series of small molecule inhibitors of TTK. Compounds are highly selective and potent inhibitors of cell proliferation. Crystal structures of TTK in complex with inhibitors have been resolved at NTRC and are available to guide the design of new inhibitors. The ER will synthesize and optimize novel TTK inhibitors and design and synthesize inhibitors of other kinases involved in aneuploidy. The inhibitors will be profiled in biochemical and cellular assays and tested in combination with other chemotherapeutic agents. Once optimized, tested in animal models available at academic collaborators in the project.

Objectives:

- Determination of the clinical value of TTK inhibition in mouse models using small molecule compounds.

- Design and synthesis of novel inhibitors of aneuploidy-modulating enzymes.



Supervisor: Rogier Buijsman