Design, synthesis and biological evaluation of a series of new, potent FLT3 PROTAC degraders with rigid linkers.

Fms-like tyrosine kinase 3 (FLT3), a member of the type III receptor tyrosine kinase family, is identified as a promising drug target for treatment of acute myeloid leukemia (AML). Here, we designed and synthesized a series of new FLT3 PROTAC degraders by incorporating rigid linkers between gilteritinib and CRBN ligand. Among them, ZLC6-49 and ZLC10-3 were identified as the most potent degraders with DC50 values of 0.74 nM and 1.28 nM, and Dmax values of 85% and 88%, respectively. Mechanistic studies demonstrated that ZLC6-49 and ZLC10-3 induce FLT3 degradation in a cereblon- and proteasome-dependent manner. Furthermore, ZLC6-49 and ZLC10-3 potently inhibit FLT3 downstream signaling, suppress cell proliferation, induce apoptosis and G0/G1-phase arrest in MV4-11 cells.