Immunomodulatory drugs (IMiDs), a new class of anti cancer d...

created [InstanceEdit:9681225] Jassal, Bijay, 2020-04-01
dbId 9681191
displayName Immunomodulatory drugs (IMiDs), a new class of anti cancer d...
literatureReference
modified [InstanceEdit:9685624] Jassal, Bijay, 2020-04-24
schemaClass Summation
text Immunomodulatory drugs (IMiDs), a new class of anti cancer drug derived from thalidomide, exert potent anti cancer effects. IMiDs bind to cereblon (CRBN), a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 (encoding transcription factors Ikaros and Aiolos) in multiple myeloma cells, contributing to their anti myeloma activity (Ito & Handa 2016, 2019, Asatsuma Okumura et al. 2019).

Thalidomide and anti inflammatory mediator therapy are being evaluated for clinical efficacy in patients with severe COVID-19. These combine the immunosuppressive action of thalidomide with the anti inflammatory actions of glucocorticoids and COX inhibition (clinical trials NCT04273529 and NCT04273581).

Additional thalidomide analogues have activities that suggest possible roles for them in COVID-19 treatments although we have not annotated them here. Pomalidomide and lenalidomide act as immunomodulatory antineoplastic agents. Their primary target is CRBN. They bind to this target and inhibit ubiquitin ligase activity (Lopez Girona et al. 2012). IKZF1 and IKZF3 are susceptibility loci for systemic lupus erythematosus (SLE). Iberdomide (CC 220), a CRBN modulator with higher binding affinity than other IMiDs, targets a greater degradation of Ikaros and Aiolos than other IMiDs (Matyskiela et al. 2018, Schafer et al. 2018). Avadomide, currently in clinical studies, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B cell lymphoma (DLBCL) (Hagner et al. 2015), advanced solid tumors, non Hodgkin lymphoma (NHL) and multiple myeloma (Rasco et al. 2019).
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