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.