Discovery of Potent Dual PROTAC Degraders Targeting BET-Kinase To Overcome FLT3 Inhibitor Resistance

FMS-like tyrosine kinase 3 (FLT3) is a validated therapeutic
target
in acute myeloid leukemia (AML). However, numerous single-agent FLT3
or multitarget inhibitors fail to achieve complete and sustained suppression
of FLT3 signaling due to the development of drug resistance. Herein,
we report the design, synthesis, and evaluation of a novel series
of dual BET-kinase degraders targeting FLT3, JAK2, and BRD4. Optimization
led to 13e, which efficiently degraded FLT3, JAK2, and
BRD4 in MV4;11 cells with DC50 values of 5.23, 0.678, and
1.17 nM, respectively. Mechanistic studies confirmed cereblon- and
proteasome-dependent degradation. 13e significantly inhibited
MV4;11 cell proliferation and demonstrated promising antitumor activity
in an MV4;11 xenograft model. Additionally, 13e showed
enhanced antiproliferative activity against FLT3 mutant-transformed
Ba/F3 cells, indicating its potential to overcome resistance. Collectively, 13e represents a highly promising FLT3/JAK2/BRD4 degrader
with potent antileukemic activity and the ability to overcome resistance
associated with current FLT3 inhibitors.