Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases
Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases
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免疫蛋白酶体选择性抑制剂：作为血液恶性肿瘤和自身免疫性疾病潜在药物的最新进展概述
DOI：
10.1016/j.ejmech.2019.111646
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发表时间：
2019
影响因子：
6.7
通讯作者：
Zhang Jiankang
中科院分区：
文献类型：
--
作者：
Xi Jianjun;Zhuang Rangxiao;Kong Limin;He Ruoyu;Zhu Huajian;Zhang Jiankang
免疫蛋白酶体是蛋白酶体的一种特殊形式，主要表达于有颌脊椎动物的淋巴细胞和单核细胞中，负责产生细胞免疫所需的抗原肽。免疫蛋白酶体的过度表达已在包括恶性肿瘤、自身免疫性疾病和炎性疾病在内的广泛疾病中被检测到。随着组成型蛋白酶体抑制剂硼替佐米、卡非佐米和伊克赛的成功获批，以及免疫蛋白酶体晶体结构和功能的阐明，多种免疫蛋白酶体抑制剂被发现或合理开发。不仅是抑制活性，免疫蛋白酶体相对于组成型蛋白酶体的选择性对于这些类似物的临床潜力至关重要，这一点已通过免疫蛋白酶体选择性抑制剂KZR-616治疗系统性红斑狼疮的临床评价得到验证。本文综述了免疫蛋白酶体抑制剂的结构、功能以及目前的研究进展，以期对免疫蛋白酶体抑制剂的研究有所帮助。
The immunoproteasome, a specialized form of proteasome, is mainly expressed in lymphocytes and monocytes of jawed vertebrates and responsible for the generation of antigenic peptides for cell-mediated immunity. Overexpression of immunoproteasome have been detected in a wide range of diseases including malignancies, autoimmune and inflammatory diseases. Following the successful approval of constitutive proteasome inhibitors bortezomib, carfilzomib and Ixazomib, and with the clarification of immunoproteasome crystal structure and functions, a variety of immunoproteasome inhibitors were discovered or rationally developed. Not only the inhibitory activities, the selectivities for immunoproteasome over constitutive proteasome are essential for the clinical potential of these analogues, which has been validated by the clinical evaluation of immunoproteasome-selective inhibitor KZR-616 for the treatment of systemic lupus erythematosus. In this review, structure, function as well as the current developments of various inhibitors against immunoproteasome are going to be summarized, which help to fully understand the target for drug discovery.