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.