Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT

In modern cancer therapy, the use
of small organic molecules against
receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy.
The association of cancer cells with dysregulated signaling pathways
linked to RTKs represents a key element in targeted cancer therapies.
The tyrosine kinase mast/stem cell growth factor receptor KIT is an
example of a clinically relevant RTK. KIT is targeted for cancer therapy
in gastrointestinal stromal tumors (GISTs) and chronic myelogenous
leukemia (CML). However, acquired resistance mutations within the
catalytic domain decrease the efficacy of this strategy and are the
most common cause of failed therapy. Here, we present the structure-based
design and synthesis of novel type II kinase inhibitors to overcome
these mutations in KIT. Biochemical and cellular studies revealed
promising molecules for the inhibition of mutated KIT.