Einsele Hermann
Department of Internal Medicine II, University Hospital Würzburg, Josef-Schneider Strasse 2, Würzburg, 97080, Germany.
Recent Results Cancer Res. 2010;184:173-87. doi: 10.1007/978-3-642-01222-8_12.
The ubiquitin-mediated degradation of proteins in numerous cellular processes, such as turnover and quality control of proteins, cell cycle and apoptosis, transcription and cell signaling, immune response and antigen presentation, and inflammation and development makes the ubiquitin-proteosome systems a very interesting target for various therapeutic interventions. Proteosome inhibitors were first synthesized as tools to probe the function and specificity of this particle's proteolytic activities. Most synthetic inhibitors rely on a peptide base, which mimics a protein substrate, attached at a COOH terminal "warhead". Notable warheads include boronic acids, such as Bortezomib and epoxyketones, such as carfilzomib. A variety of natural products also inhibit the proteosome that are not peptide-based, most notably lactacystin, that is related to NPI-0052, or salinosporamide A, another inhibitor in clinical trials. The possibility that proteosome inhibitors could be drug candidates was considered after studies showed that they induced apoptosis in leukemic cell lines. The first proteasome inhibitor in clinical application, Bortezomib showed activity in non small cell lung and androgen-independent prostate carcinoma, as well as MM and mantle cell and follicular non-Hodgkin's lymphoma. It is now lincensed for the treatment of newly diagnosed as well as relapsed/progressive MM and has had a major impact on the improvement in the treatment of MM in the last few years.
泛素介导的蛋白质降解参与众多细胞过程，如蛋白质的周转与质量控制、细胞周期与凋亡、转录与细胞信号传导、免疫反应与抗原呈递以及炎症与发育，这使得泛素 - 蛋白酶体系统成为各种治疗干预的一个非常有吸引力的靶点。蛋白酶体抑制剂最初是作为探测该颗粒蛋白水解活性的功能和特异性的工具而合成的。大多数合成抑制剂依赖于一个肽基，它模拟蛋白质底物，连接在COOH末端的“弹头”上。值得注意的弹头包括硼酸，如硼替佐米，以及环氧酮，如卡非佐米。多种天然产物也能抑制蛋白酶体，它们不是基于肽的，最显著的是与NPI - 0052相关的乳胞素，或另一种处于临床试验阶段的抑制剂沙利诺酰胺A。在研究表明蛋白酶体抑制剂可诱导白血病细胞系凋亡后，人们开始考虑其作为候选药物的可能性。临床应用中的首个蛋白酶体抑制剂硼替佐米在非小细胞肺癌、雄激素非依赖性前列腺癌以及多发性骨髓瘤、套细胞和滤泡性非霍奇金淋巴瘤中显示出活性。它现已被批准用于治疗新诊断的以及复发/进展性多发性骨髓瘤，并且在过去几年中对多发性骨髓瘤治疗的改善产生了重大影响。
