Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting
chimeras (PROTACs) represent a promising approach to eliminate the
resistance of FLT3 inhibitors. However, due to the poor druggability
of PROTACs, the development of orally bioavailable FLT3-PROTACs faces
great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered
through reasonable design. A20 selectively inhibited
the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML)
cells and potently induced FLT3-ITD degradation through the ubiquitin–proteasome
system. Notably, oral administration of A20 resulted
in complete tumor regression on subcutaneous AML xenograft models.
Furthermore, on systemic AML xenograft models, A20 could
completely eliminate the CD45+CD33+ human leukemic
cells in murine and significantly prolonged the survival time of mice.
Most importantly, A20 exerted significantly improved
antiproliferative activity against drug-resistant AML cells compared
to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory
AML.