Discovery of degrader for FLT3, GSPT1 and IKZF1/3 proteins merging PROTAC and molecular glue targeting FLT3-ITD mutant acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase expressed in hematopoietic progenitor cells and in most AML cell lines. Pharmacological inhibition of FLT3 enzymatic function is now a well-established strategy for the treatment of patients with these malignancies. Herein, we report the discovery and characterization of a FLT3 degrader A2. By design, A2 also mediates the degradation of transcription factors GSPT1 and IKZF1/3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. Importantly, A2 exhibited significantly enhanced antiproliferative activity against drug-resistant AML cells compared to Gilteritinib (MV-4-11: IC = 1.67 ± 0.14 nM vs IC = 6.52 ± 1.20 nM). Furthermore, A2 with the rigid linker demonstrated improved some pharmacokinetic properties such as half-life (T), which were achieved through rational design. Overall, A2 achieves concurrent degradation of these proteins by functioning as both PROTAC and molecular glue.