Design, synthesis and evaluation of antiproliferative effects of ferritin-targeted degraders

Ferritin is composed of H-subunits and L-subunits and serves as one of the key regulators in the iron homeostasis network. In malignant tumor cells, ferritin is highly expressed and plays a critical role in the growth and proliferation of tumor cells. Therefore, developing targeted degraders of ferritin may represent a novel therapeutic strategy for cancer treatment. In this study, through high-throughput virtual screening, we identified a small-molecule ligand, AY-1, targeting the H-subunit of ferritin. Based on this ligand, two series comprising a total of 10 molecules were designed and synthesized using PROTAC and ATTEC strategies. Experimental results demonstrated that AY-4 exhibits a binding affinity (K_d) of 3.17 nM for the H-subunit of ferritin. At a concentration of 50 μM, AY-4 effectively upregulated the levels of ferrous (Fe²⁺) and ferric (Fe³⁺) ions in cells. Furthermore, when combined with artesunate and the CDK 4/6 inhibitor palbociclib, both AY-4 and AY-9 at 50 μM enhanced the anti-proliferative activity of artesunate and palbociclib.