CRBN binds IMiDs

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).<br><br>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).<br><br>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).

免疫调节药物（IMiDs），一类源自沙利度胺的新型抗癌药物，展现出显著的抗癌效果。IMiDs通过与CRL4 E3连接酶的底物受体cereblon（CRBN）结合，诱导多发性骨髓瘤细胞中IKZF1和IKZF3（编码转录因子Ikaros和Aiolos）的泛素化和降解，从而发挥其抗骨髓瘤活性（Ito & Handa 2016, 2019, Asatsuma Okumura et al. 2019）。沙利度胺与抗炎介质治疗正在评估其在重症COVID-19患者中的临床疗效。这些药物结合了沙利度胺的免疫抑制作用与糖皮质激素和COX抑制的抗炎作用（临床试验NCT04273529和NCT04273581）。此外，尚有沙利度胺类似物显示出在COVID-19治疗中可能发挥作用的潜力，尽管此处未对其进行标注。Pomalidomide和lenalidomide作为免疫调节抗肿瘤药物，其主要靶点是CRBN。它们与该靶点结合并抑制泛素连接酶活性（Lopez Girona et al. 2012）。IKZF1和IKZF3是系统性红斑狼疮（SLE）的易感位点。Iberdomide（CC 220），一种比其他IMiDs具有更高结合亲和力的CRBN调节剂，能够诱导比其他IMiDs更大量的Ikaros和Aiolos降解（Matyskiela et al. 2018, Schafer et al. 2018）。Avadomide目前正在临床研究中，它通过与CRBN结合，促进弥漫大B细胞淋巴瘤（DLBCL）、晚期实体瘤、非霍奇金淋巴瘤（NHL）和骨髓瘤中的Aiolos和Ikaros的降解（Hagner et al. 2015, Rasco et al. 2019）。