The dysregulation of pathways regulating cellular function is a frequent hallmark of cancer and the development of specific pathway inhibitors that alter tumor growth and progression are the focus of multiple recent studies. E3 ubiquitin ligases are a large group of diverse protein enzymes that specifically target proteins for clearance, and their importance to normal cellular function is illustrated in the many diseases associated with their loss of function or inappropriate targeting. S-phase kinase-associated protein 2 (Skp2) is an F box protein that plays critical roles in cell-cycle progression, senescence, metabolism, and acts as an Skp1–Cullin-1–F box (SCF) ubiquitin ligase substrate recognition factor. Overexpression of Skp2 is associated with poor prognosis and metastasis in many cancers and is a well validated drug target. In a recent report, Chan et al. have identified an Skp2 inhibitor that selectively impairs Skp2 E3 ligase activity using an integrated virtual high-throughput drug screening and experimental validation approach. This Skp2 inhibitor restricts cancer stemness and potentiates sensitivity to chemotherapeutic agents in multiple animal tumor models. These findings identify a new novel small molecule that targets the Skp2 and reduces tumor growth by attenuating aerobic glycolysis and inducing cellular senescence.

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