Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

Abstract

Immunomodulatory drugs (IMiDs), today also known as cereblon (CRBN) binding drugs, are therapeutically important anti-cancer and anti-inflammatory drugs. IMiDs are analogs of their prototype compound thalidomide. IMiDs have immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. CRBN is a component and substrate receptor of the Cullin 4 Ring E3 Ubiquitin Protein Ligase complex (CRL4). CRL4 consists of Cullin 4, RING finger protein (Roc1), and DNA damage binding protein 1 (DDB1). CRBN binds to its substrate proteins and it leads to ubiquitination of these substrates by the CRL4. CRBN is also involved in IMiDs-mediated T-cell co-stimulation and cytokine production. CRBN is a primary target of thalidomide teratogenicity. The binding of IMiDs to CRBN is associated with cytotoxicity of IMiDs and is used to treat multiple myeloma (MM), myelodysplastic syndromes (MDS), lymphomas and chronic lymphocytic leukemia. CRBN is composed of an N-terminal ATP-dependent serine protease Lon-like domain, which links to the E3 ubiquitin protein ligase complex CRL4, and a C-terminal domain, which binds IMiDs. CRBN binding is mediated by a glutarimide ring in thalidomide, lenalidomide, pomalidomide, CC-122, CC-220, CC-885 and CC-90009. Development of effector molecules mediating targeted ubiquitination of disease related proteins through cereblon is a new important way in pharmacology.

Rapid Progress in the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma

“…Lenalidomide (CC-5013) is the 4-amino-glutamyl analogue of thalidomide. Unlike thalidomide, lenalidomide is not sedative, and the incidence of sensory axonal neuropathy is less frequent, but still possible [13,14].…”

Cereblon gene variants and clinical outcome in multiple myeloma patients treated with lenalidomide

“…Thalidomide and its derivatives, the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide, are used to treat several hematological malignancies, including multiple myeloma (MM) 1,2 . Although only 30% of patients respond to IMiDs used as single agents 3 , triplet combination therapies involving a proteasome inhibitor (carfilzomib), immunomodulatory agent (lenalidomide), and a corticosteroid (dexamethasone) are clinically effective, yielding complete or deep responses in patients with newly diagnosed multiple myeloma (NDMM) 4,5 and relapsed or refractory MM 6 .…”

“…The anti-myeloma activity of IMiDs has been attributed to several mechanisms of action, including anti-angiogenic, pro-apoptotic, and anti-proliferative effects 1,7 . Until recently, however, the precise molecular mechanisms by which thalidomide and its analogs act remained elusive.…”

“…First identified in patients with non-syndromic mental retardation 10 , CRBN has since been studied in vitro in MM, myelodysplastic syndrome, and lymphoma cell lines 9 , in vivo using zebrafish, chick, and rodent animal models 8,11–14 , and in pre- and post-IMiD treatment tissue samples collected from patients with MM 3 . Upon binding to cereblon, IMiDs induce CRBN-dependent proteasomal degradation and inhibition of IKZF1/3, B cell-specific transcription factors required for both myeloma cell viability and activation of the immune system 1,2,7 .…”