VHL and cancer: Recent strategies involve the development of small-molecule inhibitors to block E3 activity (e.g., MDM2 inhibitors like Nutlins, Navtemadlin, and Milademetan, which show activity in specific cancers but face toxicity/resistance issues) and utilizing Proteolysis-Targeting Chimeras (PROTACs) to hijack E3 ligases (like VHL or CRBN) to promote the degradation of oncogenic proteins (e.g., AR/ER degraders showing promise in clinical trials).