创新链/学科链/研发链/产业链

新药研发前沿动态 / 医药领域趋势进展

CELMoDs类IKZF1/3降解剂的研究进展

Advances in Research on CELMoDs IKZF1/3 Degraders

  • 摘要: IKZF1 (Ikaros)和IKZF3 (Aiolos)是一种锌指转录因子,涉及多种信号通路和调节机制,对免疫细胞发育和内环境稳定尤为关键。IKZF1/3过度表达与多种血液系统恶性肿瘤的发生和发展密切相关。免疫调节药物(IMiDs)通过与cereblon(CRBN)E3连接酶相互作用降解IKZF1/3,其在临床上与其他药物如蛋白酶体抑制剂、单克隆抗体等联用被用来治疗多发性骨髓瘤、非霍奇金淋巴瘤等肿瘤。然而,上述疗法对于复发性/难治性肿瘤的效果不佳,存在未被满足的巨大临床需求。CRBN E3泛素连接酶调节剂(CELMoDs)作为一种新型免疫调节药物,能够更有效、更深度地降解IKZF1/3,显示出良好体内外活性,其中多个化合物已经进入临床研究。通过对CELMoDs类IKZF1/3降解剂的研究进展进行综述,以期为抗血液肿瘤药物的开发提供参考。

     

    Abstract: IKZF1 (Ikaros) and IKZF3 (Aiolos) are zinc finger transcription factors, which involve a variety of signal pathways and regulatory mechanisms, and are particularly critical to the development of immune cells and the stability of the internal environment. The overexpression of IKZF1/3 is closely related to the occurrence and development of a variety of hematological malignancies. Immunomodulatory drugs (IMiDs) degrade IKZF1/3 by interacting with cereblon (CRBN) E3 ligase. In clinical practice, IMiDs in combination with other drugs such as proteasome inhibitors and monoclonal antibodies, are applied for the treatment of multiple myeloma, non-Hodgkin's lymphoma and other cancers. However, the above strategy for recurrent/refractory tumors is not satisfactory, and there is still a huge unmet clinical demand. CRBN E3 ubiquitin ligase modulators (CELMoDs), a new type of novel immunomodulatory drugs, can degrade IKZF1/3 more effectively and deeply, and show its superiority in in vitro and in vivo trials. Quite a few CELMoDs have entered clinical evaluation. This paper reviews the research progress of CELMoDs IKZF1/3 degraders in order to provide some reference for the development of anti-hematologic tumor drugs.

     

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