CELMoDs类IKZF_(1/3)降解剂的研究进展  

Advances in Research on CELMoDs IKZF_(1/3)Degraders

作　　者：吴雄 焦宇 吕仕铭 陈亚东 梅德盛 WU Xiong;JIAO Yu;LYU Shiming;CHEN Yadong;MEI Desheng(Suzhou Guokuang PharmTech.Co.,Ltd,Suzhou 215000,China;School of Science,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]苏州国匡医药科技有限公司,江苏苏州215000 [2]中国药科大学理学院,江苏南京211198

出　　处：《药学进展》2023年第1期66-74,共9页Progress in Pharmaceutical Sciences

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。IKZF_(1/3)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IKZF_(1/3),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IKZF_(1/3),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IKZF_(1/3)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。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 IKZF_(1/3)is closely related to the occurrence and development of a variety of hematological malignancies.Immunomodulatory drugs(IMiDs)degrade IKZF_(1/3)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 IKZF_(1/3)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 IKZF_(1/3)degraders in order to provide some reference for the development of anti-hematologic tumor drugs.

关 键 词：IKZF_(1/3) 肿瘤 免疫调节药物 CRBN E3泛素连接酶调节剂 

分 类 号：R730.5[医药卫生—肿瘤]