Enhancing Antiproliferative Activity and Selectivity of a FLT‑3 Inhibitor by Proteolysis Targeting Chimera Conversion

The receptor tyrosine kinase FLT-3
is frequently mutated in acute
myeloid leukemia; however, current small molecule inhibitors suffer
from limited efficacy in the clinic. Conversion of a FLT-3 inhibitor
(quizartinib) into a proteolysis targeting chimera (PROTAC) results
in a compound that induces degradation of FLT-3 ITD mutant at low
nanomolar concentrations. Furthermore, the PROTAC is capable of inhibiting
cell growth more potently than the warhead alone while inhibiting
fewer off-target kinases. This enhanced antiproliferative activity
occurs, despite a slight reduction in the PROTAC’s kinase inhibitory
activity, via an increased level of apoptosis induction suggesting
nonkinase roles for the FLT-3 ITD protein. Additionally, the PROTAC
is capable of inducing FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3 ITD may provide
a useful method for therapeutic intervention.