Safety considerations for cereblon-recruiting targeted protein degraders

Targeted protein degraders (TPDs) that recruit the E3 ligase cereblon (CRBN) include two innovative drug classes: molecular glue degraders and proteolysis targeting chimeras. These TPDs have shown great promise in addressing difficult drug targets in oncologic and non-oncologic diseases; however, as well as inducing proteosomal degradation of their therapeutic target, they can also lead to degradation of unintended CRBN neosubstrates. This is a major safety consideration because many CRBN-recruiting TPDs are structurally related to thalidomide and other immunomodulatory imide drugs that are known to be teratogenic. The teratogenic effect of immunomodulatory imide drugs is due in part to their induction of CRBN-mediated neosubstrate degradation. Therefore, there is a need for a scientific consensus on rigorous, consistent and effective methods to assess the safety of CRBN-recruiting TPDs. Here, we provide an overview of the endogenous functions and substrates of CRBN as well as of the role of CRBN as the effector of immunomodulatory imide drugs, next-generation molecular glue degraders and proteolysis targeting chimeras. We discuss how degradation of unintended 'off-target' CRBN neosubstrates could potentially cause toxicity or safety liabilities in multiple organ systems as well as induce teratogenic effects. We outline key safety considerations for the development of CRBN-recruiting TPDs and suggest best practices for monitoring on-target versus off-target degradation.