VHL-based PROTACs developed to knockdown BRD4, a recognized BET protein involved in malignant tumors [19], were able to favor a cooperative interaction between the E3 ligase and POI at different lines of investigation, form a large protein–protein interaction surface identified by X-ray crystallography to the direct quantification of Kdbinary and Kdternary by isothermal calorimetry titration (ITC) [16,20]. The gene discussed is VHL; the disease is cancer.