Mezigomide is an oral cereblon E3 ligase modulator (CELMoD) that is under clinical investigation in patients with relapsed/refractory (RR) multiple myeloma (MM). Like other CELMoD compounds, mezigdomide acts by altering the conformation of cereblon within the cullin 4A ring ligase–cereblon (CRL4CRBN) E3 ubiquitin ligase complex, thereby recruiting novel protein substrates for selective proteasomal degradation. These include two critical lymphoid transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), also known as Ikaros and Aiolos, which have important roles in the development and differentiation of hematopoietic cells, in MM pathobiology, and in suppressing the expression of interferon-stimulating genes and T-cell stimulation. Among the CELMoDs, mezigdomide has the greatest cereblon-binding potency, plus the greatest potency for the degradation of Ikaros and Aiolos and subsequent downstream antimyeloma effects. Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM.
美齐戈米德是一种口服的Cereblon E3连接酶调节剂（CELMoD），目前正在复发/难治性多发性骨髓瘤患者中进行临床研究。与其他CELMoD化合物类似，美齐戈米德通过改变Cullin 4A环连接酶-Cereblon（CRL4CRBN）E3泛素连接酶复合物中Cereblon的构象发挥作用，从而募集新型蛋白质底物进行选择性蛋白酶体降解。这些底物包括两个关键的淋巴样转录因子——Ikaros家族锌指蛋白1和3（IKZF1和IKZF3，亦称为Ikaros和Aiolos），它们在造血细胞的发育与分化、多发性骨髓瘤的病理生物学过程以及抑制干扰素刺激基因表达和T细胞活化中具有重要作用。在CELMoD类药物中，美齐戈米德具有最强的Cereblon结合效力，同时对Ikaros和Aiolos的降解能力及后续下游抗骨髓瘤效应也最为显著。临床前研究证实，美齐戈米德在多发性骨髓瘤中具有抗增殖和促凋亡作用，同时兼具免疫刺激效应，并能与其他抗骨髓瘤药物（包括对来那度胺/泊马度胺耐药的骨髓瘤细胞系和小鼠异种移植模型）产生协同活性。早期临床试验数据显示，该药物在经深度治疗的复发/难治性多发性骨髓瘤患者（包括三类药物难治性患者）中表现出显著活性，且安全谱可耐受、可管理。本综述系统总结了美齐戈米德当前的临床前与临床研究进展，并探讨其在多发性骨髓瘤治疗中的未来潜在应用价值。
肿瘤(癌症)患者之家