Mechanisms of action of immunomodulatory drugs — from teratogenicity to treatment of multiple myeloma

Abstract

Introduction. Immunomodulatory drugs (IMiDs) are a class of chemical derivatives of thalidomide with numerous immunomodulatory, antiangiogenic, anti-inflammatory, and cytostatic effects in multiple myeloma (MM).Aim — to highlight the history of the discovery of IMiDs and discuss the molecular mechanisms of their therapeutic activity.Basic information. In 2010, more than half a century after the German company Chemie Grünenthal began the clinical use of thalidomide, the first understanding of the molecular mechanism of thalidomide and its structural derivatives appeared. Hiroshi Handa and colleagues from the Tokyo Medical University discovered that the drug thalidomide binds to the protein Cereblon (CRBN), a substrate receptor of the CRL4CRBN E3 ubiquitin ligase. Subsequent generations of immunomodulatory drugs (IMiDs) — lenalidomide and pomalidomide, are structurally like thalidomide. The glutarimide ring of IMiDs is inserted into the receptor pocket of the CRBN. In this case, the variable phthalimide part of the drug protrudes from the binding domain, changing the configuration of the CRBN in such a way that it allows it to interact with proteins (neosubstrates) with which it does not react under physiological conditions. It was later found that ubiquitin-mediated degradation of two transcription factors (Ikaros and Aiolos) underlies the antitumor and immunomodulatory activity of IMiDs, which have shown unique clinical efficacy in the treatment of multiple myeloma. A natural continuation of the success of IMiDs was the creation of a series of therapeutic molecules (Iberdomide, etc.) belonging to a new class of drugs called CELMoDs (Cereblon E3 Ligase Modulating Drugs). The presented literature review is devoted to the history of the discovery of IMiDs and a discussion of the molecular mechanisms of their therapeutic activity.