Discovery of Potent Dual PROTAC Degraders Targeting BET-Kinase To Overcome FLT3 Inhibitor Resistance

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Novel dual BET-kinase degraders show antileukemic activity in AML, indicating potential to overcome FLT3 resistance.

The discovery of dual PROTAC degraders targeting FLT3 and JAK2 can address drug resistance in AML.
Degrader 13e demonstrated effective degradation of FLT3, JAK2, and BRD4 with DC50 values of 5.23, 0.678, and 1.17 nM.
Mechanistic studies confirmed the role of cereblon and the proteasome in the degradation process.
The potent antileukemic activity of 13e suggests a promising new option for patients with FLT3 inhibitor resistance.

Xiang et al. (2025) studied this question.

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