Hartley-Brown Monique A, Mo Clifton C, Nadeem Omar, Midha Shonali, Laubach Jacob P, Richardson Paul G
Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, 450 Brookline Avenue, Dana 1B02, Boston, MA 02115, USA.
Cancers (Basel). 2024 Mar 15;16(6):1166. doi: 10.3390/cancers16061166.
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脑啡肽 E3 连接酶调节剂（CELMoD），目前正在复发/难治性（RR）多发性骨髓瘤（MM）患者中进行临床研究。与其他 CELMoD 化合物一样，美齐戈米德通过改变 Cullin 4A 环连接酶-脑啡肽（CRL4CRBN）E3 泛素连接酶复合物中脑啡肽的构象来发挥作用，从而募集新的蛋白质底物进行选择性蛋白酶体降解。其中包括两个关键的淋巴样转录因子，即 Ikaros 家族锌指蛋白 1 和 3（IKZF1 和 IKZF3），也称为 Ikaros 和 Aiolos，它们在造血细胞的发育和分化、MM 病理生物学以及抑制干扰素刺激基因的表达和 T 细胞刺激中发挥重要作用。在 CELMoD 中，美齐戈米德具有最强的脑啡肽结合能力，以及最强的降解 Ikaros 和 Aiolos 的能力以及随后的下游抗骨髓瘤作用。美齐戈米德的临床前研究已证明其在 MM 中的抗增殖和凋亡作用，以及其免疫刺激作用和与其他抗骨髓瘤药物的协同活性，包括在来那度胺/泊马度胺耐药的 MM 细胞系和小鼠异种移植模型中。早期临床试验数据表明，在 RRMM 的重度预处理患者中，包括那些对三类药物难治的患者，美齐戈米德具有显著活性，同时具有可耐受和可管理的安全性。本综述总结了美齐戈米德目前的临床前和临床研究结果及其在 MM 治疗中潜在的未来作用。
