Deregulation of F-box proteins and their substrates contributes to malignant transformation since the misregulated degradation of tumor suppressors or oncoproteins can drive tumorigenesis. One of our goals is to understand the functions of key CRLs whose deregulation contributes to the oncogenic phenotype and develop a novel therapeutic strategy that exploits these aberrations to kill cancer cells. Moreover, we are inspired by the clinical success of thalidomide and other immunomodulatory drugs (IMiDs) which are used in the treatment of multiple myeloma. IMiDs target CRBN, a substrate receptor of a CRL4 complex, and repurpose its activity towards oncogenic cellular substrates. Thus, IMiDs allow CRBN to bind neo-substrates, acting as a molecular glue. Our long-term goal is to develop new anticancer therapies based on these concepts. In particular, we are working towards the identification of small molecule glues able to promote the proteolysis of untargetable oncoproteins.