Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML

FLT3
inhibitors (FLT3i) are effective for treating acute myeloid
leukemia (AML), but acquired and adaptive resistance pose significant
challenges. Therefore, finding a novel AML therapy that overcomes
resistance is necessary. Proteolysis-targeting chimeras (PROTACs)
are a new approach in drug discovery, offering a promising strategy
for targeting FLT3 mutations in the development of effective anti-AML
therapies. Our previous study found that simultaneously targeting
FLT3 and CHK1 can upregulate p53 level and downregulate c-Myc level,
thus overcoming adaptive resistance. We combined the merits of both
PROTACs and dual targeting drugs to design a series of dual FLT3/CHK1
PROTACs. The optimal compound A28 effectively degraded
FLT3 and CHK1 in a proteasome-dependent manner. Also, A28 potently inhibited FLT3 signaling, downregulated c-Myc, and upregulated
p53 level. Further studies indicated that A28 had the
potential to overcome acquired and adaptive resistance. Importantly,
weekly intravenous administration of A28 sustained tumor
growth suppression in MV-4–11 subcutaneous xenograft models.