Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor

Monopolar
spindle kinase 1 (MPS1/TTK) is a key element of the mitotic
checkpoint and clinically evaluated as a target in the treatment of
aggressive tumors such as triple-negative breast cancer. While long
drug–target residence times have been suggested to be beneficial
in the context of therapeutic MPS1 inhibition, no irreversible inhibitors
have been reported. Here we present the design and characterization
of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase’s hinge
region. RMS-07 shows potent MPS1 inhibitory activity
and selectivity against all protein kinases with an equivalent cysteine
but also in a broader kinase panel. We demonstrate potent cellular
target engagement and pronounced activity against various cancer cell
lines. The covalent binding mode was validated by mass spectrometry
and an X-ray crystal structure. This proof of MPS1 covalent ligandability
may open new avenues for the design of MPS1-specific chemical probes
or drugs.