PROTACFLT-3degrader 4 is an orally active CRBN-based FLT3-PROTAC degrader that efficiently induces the degradation of FLT3-ITD via the ubiquitin-proteasome system. It demonstrates high selectivity for FLT3-ITD mutant acute myeloid leukemia (AML) cells. [Blue: CRBN ligand, Black: linker; Pink: FLT3 inhibitor].

PROTAC FLT-3 degrader 4 (compound A20) exhibits antiproliferative activity against MV4-11 and MOLM-13 cells, with IC50 values of 39.9 nM and 169.9 nM, respectively [1]. At concentrations ranging from 0.25 to 100 nM over 24 hours, it significantly reduces FLT3-ITD protein levels in these cells [1]. Additionally, at 20 nM over 12 hours, it inhibits the phosphorylation of FLT3-ITD and downstream mediators such as STAT5, S6K, and ERK [1]. The compound also induces G1 phase cell cycle arrest in a dose-dependent manner and promotes apoptosis in MV4-11 and MOLM-13 cells [1].

PROTAC FLT-3 degrader 4 (compound A20; 1.235-10 mg/kg; oral; daily; for 2 weeks) effectively suppresses tumor growth at a dose of 1.25 mg/kg. At 5 mg/kg, tumor regression is observed with a tumor growth inhibition (TGI) of 97.5%, and complete tumor regression occurs at 10 mg/kg [1]. The pharmacokinetic parameters of PROTAC FLT-3 degrader 4 in Sprague-Dawley rats are as follows: 1.19 parameter iv (1 mg/kg) po (10 mg/kg) with AUC 0-t (h·ng/mL) at 2768.1 and 14705.3, C max (ng/mL) at 1117.5, Tmax (h) at 6.2, T1/2 (h) at 6.5 and 3.8, V ss (L/kg) at 3.5 and 5.7, CL (mL/min/kg) at 5.5 and 11.2, and bioavailability (F%) at 53. Animal Model: Four-week-old male nu/nu mice injected with MV4-11 cells [1]. Dosages administered were 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg, and 10 mg/kg, orally, daily for 2 weeks. Result: Tumor growth was significantly inhibited at a 1.25 mg/kg dose.