PROTACFTO degrader 1 is a PROTAC designed to target and degrade fat mass and obesity-associated protein (FTO). It leverages the VHL E3 ligase and the ubiquitin-proteasome system for the selective degradation of FTO. This compound enhances m6A modifications on mRNAs related to ribosome biogenesis and promotes their YTHDF2-mediated degradation. Furthermore, PROTACFTO degrader 1 effectively inhibits cancer cell proliferation and induces apoptosis, making it a valuable candidate for cancer research, particularly in acute myeloid leukemia (AML).

PROTAC FTO degrader 1 (Compound FP54) effectively degrades FTO in NB4 and MOLM-13 cells in a dose-dependent manner with a maximum degradation rate of over 95% when used at concentrations of 0.08-2.5 μM over 48 hours. This compound inhibits the proliferation of various acute myeloid leukemia cell lines with IC50 values ranging from 0.48 to 2.44 μM. Additionally, at concentrations of 2-5 μM for 48 hours, it significantly induces apoptosis in MOLM-13 and NB4 cells. When used at 5 μM, it promotes differentiation in MOLM-13 cells. At 2 μM for 48 hours, it enhances the mRNA m6A modification levels in NB4 cells and reduces the polysome/80S monosome ratio, thereby inhibiting global translation in MOLM-13 cells. Furthermore, at 2 μM, it decreases the stability of ribosome-biogenesis-related mRNA such as MRPL36 and LYAR in MOLM-13 cells by promoting YTHDF2-mediated degradation.

Compound FP54, known as PROTAC FTO degrader 1, when administered intravenously at a dose of 25 mg/kg, three times weekly, can delay disease progression and extend survival in mice with MA9.3Ras/MOLM13/AML-0148 tumors.