CRL4(CRBN) E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

SIMPLE SUMMARY: Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM) and other hematological malignancies. Cereblon (CRBN), a target of IMiDs, forms the CRL4 E3 ubiquitin ligase complex (CRL4(CRBN)) with DDB1, CUL4A and RBX1. The insight into the molecular mechanism of IMiDs action has advanced dramatically since the identification of cereblon (CRBN) as their direct target. Targeting CRBN by IMiDs modifies CRL4(CRBN) substrate specificity towards non-physiological protein targets which are subsequently ubiquitinated and degraded by the proteasome. To date, IMiDs are the only known group of protein degraders used in clinical practice. This review provides the current state of knowledge about thalidomide and its derivatives’ mechanisms of action, and highlights the future perspectives for targeted protein degraders. ABSTRACT: Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4(CRBN)) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4(CRBN) complex’s activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4(CRBN) to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future.