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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• FMS-like tyrosine kinase 3 (FLT3) is a key target in acute myeloid leukemia (AML).
• Current FLT3 inhibitors often face drug resistance, limiting their efficacy.
• Novel therapeutic strategies are needed to overcome resistance and improve AML treatment.

Purpose of the Study:

• To design, synthesize, and evaluate novel dual BET-kinase degraders targeting FLT3, JAK2, and BRD4.
• To identify a potent compound capable of overcoming resistance mechanisms in AML.
• To assess the therapeutic potential of these degraders in preclinical models.

Main Methods:

• Synthesis and chemical optimization of novel dual BET-kinase degraders.
• In vitro assessment of target degradation (FLT3, JAK2, BRD4) in AML cell lines (MV4;11).
• Evaluation of antiproliferative activity and in vivo efficacy in AML xenograft models.

Main Results:

• Compound 13e demonstrated efficient degradation of FLT3, JAK2, and BRD4 in MV4;11 cells with low nanomolar DC50 values.
• Degradation was confirmed to be cereblon- and proteasome-dependent.
• 13e significantly inhibited MV4;11 cell proliferation and showed promising antitumor activity in vivo.
• Enhanced antiproliferative effects were observed against FLT3 mutant-transformed cells, suggesting resistance-overcoming potential.

Conclusions:

• Compound 13e is a potent FLT3/JAK2/BRD4 degrader with significant antileukemic activity.
• 13e demonstrates the potential to overcome resistance associated with current FLT3 inhibitors.
• This novel degrader represents a promising therapeutic candidate for AML treatment.