From bortezomib to other inhibitors of the proteasome and beyond.
From bortezomib to other inhibitors of the proteasome and beyond.
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DOI：
10.2174/1381612811319220012
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发表时间：
2013
影响因子：
3.1
通讯作者：
Dou QP
中科院分区：
文献类型：
--
作者：
Buac D;Shen M;Schmitt S;Kona FR;Deshmukh R;Zhang Z;Neslund-Dudas C;Mitra B;Dou QP
癌症药物发现领域非常重视新的和癌症特异性分子靶标的鉴定。用于设计新型抗肿瘤药物的此类靶标的丰富来源是泛素-蛋白酶体系统（UP-S），其是一种严格调节的高度特异性途径，负责细胞内绝大多数蛋白质的周转。由于其在确保正常细胞功能的几乎所有细胞过程中的关键作用，其在一个时间点的抑制被认为是非特异性的，因此不值得作为分子药物靶标进行进一步研究。然而，今天的蛋白酶体是世纪最有前途的抗癌药物靶点之一。肿瘤细胞事实上比正常细胞对蛋白酶体抑制剂更敏感的发现确实为其抑制剂的设计铺平了道路。这些努力催生了硼替佐米，这是FDA批准的第一种蛋白酶体抑制剂，目前被用作新诊断多发性骨髓瘤（MM）、复发性/难治性MM和套细胞淋巴瘤的一线治疗。虽然成功地改善了血液恶性肿瘤患者的临床结局，但复发通常发生在最初对硼替佐米有反应的患者中。因此，硼替佐米耐药性的获得是其治疗的主要问题。此外，一些神经毒性与硼替佐米治疗相关，并且缺乏其在实体瘤中的疗效。这些观察结果鼓励研究人员追求下一代蛋白酶体抑制剂，理想情况下，它将克服硼替佐米耐药性，降低毒性和更广泛的抗癌活性。本文综述了硼替佐米的成功和局限性，并描述了该领域的最新进展，包括最值得注意的是，2012年7月FDA批准的第二代蛋白酶体抑制剂卡非佐米。其他蛋白酶体抑制剂目前在临床试验和那些目前是实验级也将进行讨论。
The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its critical role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a molecular drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clinical outcomes for patients with hematological malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been associated with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clinical trials and those that are currently experimental grade will also be discussed.
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影响因子：
168.9
作者：
Cavo, Michele;Tacchetti, Paola;Baccarani, Michele
通讯作者：
Baccarani, Michele
DOI：
10.1073/pnas.0901982106
发表时间：
2009-04-21
影响因子：
11.1
作者：
Clerc, Jerome;Groll, Michael;Kaiser, Markus
通讯作者：
Kaiser, Markus
影响因子：
--
作者：
Bogyo, M;Shin, S;Ploegh, HL
通讯作者：
Ploegh, HL
影响因子：
3.4
作者：
Colombo, Matteo;Vallese, Stefania;Guedat, Philippe
通讯作者：
Guedat, Philippe
影响因子：
5.8
作者：
Asai, A;Tsujita, T;Mizukami, T
通讯作者：
Mizukami, T