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This research investigates the molecular mechanisms of targeted proteolysis of mutant FLT3 in acute myeloid leukemia using PROTACs.

March 1, 2026مجلة محكمة النقضOpen Access

Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins

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Researchers report PROTAC-induced apoptosis of mutant FLT3 in AML, indicating a novel therapeutic approach.

This research investigates the molecular mechanisms of targeted proteolysis of mutant FLT3 in acute myeloid leukemia using PROTACs.
Utilized FLT3 PROTACs MA49 and MA50 to induce degradation of FLT3-ITD in leukemic cell lines.
Analyzed the effects on primary AML blasts and compared them to other cell types.
Investigated the role of BIM and heat shock proteins in FLT3-ITD degradation.
MA49 and MA50 significantly induced apoptosis in FLT3-ITD-positive cells (p < 0.05-0.0001).
Degradation of FLT3-ITD linked to BIM activation and depletion of chaperone proteins HSP90 and HSP110.
Higher levels of HSP90 and HSP110 correlated with reduced survival in AML patients (p < 0.1).

Halilovic et al. (2024) studied this question.

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