Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations

The development of
therapeutic resistance in the majority
of patients
limits the long-term benefit of ROS1 inhibitor treatment. On-target
mutations of the ROS1 kinase domain confer resistance to crizotinib
and lorlatinib in more than one-third of acquired resistance cases
with no current effective treatment option. As an alternative to stoichiometric
inhibition, proteolytic degradation of ROS1 could provide an effective
tool to combat resistance generated by these mutations. Our study
has identified a potent, orally active ROS1 degrader with an excellent
pharmacokinetics profile. The degrader can effectively inhibit ROS1-dependent
cell proliferation and tumor growth by degrading the ROS1 kinase,
thereby eliminating the active phospho-ROS1. More importantly, the
degradation-based therapeutic modality can overcome on-target mutation
resistance to tyrosine kinase inhibitors by efficient degradation
of the mutated kinase to achieve greater potency than inhibition.