Development of the proteasome inhihitor Veleade™ (Bortezomib)
Development of the proteasome inhihitor Veleade™ (Bortezomib)
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DOI：
10.1081/cnv-120030218
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发表时间：
2004-01-01
影响因子：
2.4
通讯作者：
Kauffman, M
中科院分区：
文献类型：
--
作者：
Adams, J;Kauffman, M
二肽硼酸类似物VELCADE(TM)（硼替佐米，以前称为PS-341、LDP-341和MLM341）是一种有效的选择性蛋白酶体抑制剂，蛋白酶体是一种多催化酶，通过降解调节蛋白或其抑制剂介导许多细胞调节信号。因此，蛋白酶体是药理学试剂的潜在靶标。硼替佐米（Bortezomib）是第一个进入临床试验的蛋白酶体抑制剂，已经在体内和体外显示出对多种恶性肿瘤的活性，包括骨髓瘤、慢性淋巴细胞白血病、前列腺癌、胰腺癌和结肠癌。该药物可迅速从血管室中清除，但一项新的药效学分析表明，硼替佐米介导的蛋白酶体阻断是剂量依赖性和可逆的。基于I期研究表明硼替佐米对晚期癌症患者具有可控的毒性，II期试验已启动用于实体和血液系统恶性肿瘤。
The dipeptide boronic acid analogue VELCADE(TM) (Bortezomib; formerly known as PS-341, LDP-341 and MLM341) is a potent and selective inhibitor of the proteasome, a multicatalytic enzyme that mediates many cellular regulatory signals by degrading regulatory proteins or their inhibitors. The proteasome, is, thus, a potential target for pharmacological agents. Bortezomib, the first proteasome inhibitor to reach clinical trials, has shown in vitro and in vivo activity against a variety of malignancies, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer. The drug is rapidly cleared from the vascular compartment, but a novel pharmacodynamic assay has shown that bortezomib-mediated proteasome blockade is dose-dependent and reversible. Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies.