FLT3 degrader MA191 shows preclinical activity against inhibitor-resistant AML cells

Researchers developed MA191, a proteolysis-targeting chimera that links FLT3 binding to recruitment of the VHL E3 ubiquitin ligase. They tested the compound in FLT3-ITD-positive AML cell lines and primary patient cells, compared it with a VHL-binding-deficient stereoisomer, and assessed effects on healthy blood and bone marrow progenitor cells. Experiments also examined resistance-associated FLT3 tyrosine kinase domain mutations, stromal-cell interactions and AML-cell proliferation in zebrafish larvae.

MA191 induced apoptosis in cultured and primary FLT3-ITD-positive AML cells, with reported IC50 values of 9.6–11 nM in cell lines and EC50 values of 0.001–0.883 μM in primary cells. FLT3-ITD degradation had greater activity than kinase inhibition in the stereoisomer comparison (p<0.03); degradation required VHL, proteasome activity, neddylation and BIM. The compound retained anti-leukemic effects despite resistance-associated mutations and stromal-cell interactions. The study reported no harm to healthy progenitors or myeloid differentiation, and no significant toxicity in the zebrafish model.

These findings support further investigation of FLT3 degradation as a strategy to address resistance to FLT3 inhibitors. Evidence is limited to laboratory, primary-cell and animal models; the source reports no human treatment outcomes or clinical trial data.