The Development and Pharmacology of Proteasome Inhibitors for the Management and Treatment of Cancer
The Development and Pharmacology of Proteasome Inhibitors for the Management and Treatment of Cancer
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DOI：
10.1016/s1054-3589(08)57003-7
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Hui, Ai-Min
中科院分区：
文献类型：
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作者：
Ruggeri, Bruce;Miknyoczki, Sheila;Hui, Ai-Min
泛素-蛋白酶体复合物是设计新型化疗药物的重要分子靶点。该复合物在信号转导途径中起关键作用，该信号转导途径对于肿瘤细胞生长和存活、细胞周期控制、转录调节以及对内源性和外源性刺激的细胞应激反应的调节是重要的。转化细胞对蛋白酶体抑制剂的敏感性和具有可耐受的（尽管狭窄）治疗指数的治疗方案的成功设计使得蛋白酶体抑制成为癌症治疗的可行策略。硼酸蛋白酶体抑制剂硼替佐米获批用于治疗多发性骨髓瘤和套细胞淋巴瘤，从而实现了蛋白酶体作为分子靶点的临床验证。几种代表不同结构类别（分别为肽基环氧酮、β-内酯和肽基硼酸）、作用机制、药理学和药效学活性特征以及治疗指数的“下一代”蛋白酶体抑制剂（卡非佐米和PR-047、NPI-0052和CEP-18770）现已进入临床开发。这些试剂可以扩展蛋白酶体抑制剂用于治疗实体瘤和用于特定非肿瘤学，即，炎症性疾病，以及适应症。本章讨论了蛋白酶体的生物学，目前在临床开发中的蛋白酶体抑制剂的药物化学和作用机制，硼替佐米的临床前和临床药理学和安全性概况以及针对血液和实体肿瘤的新化合物。本章考虑了这类新型治疗剂的研究和其他应用的未来方向。
The ubiquitin-proteasome complex is an important molecular target for the design of novel chemotherapeutics. This complex plays a critical role in signal transduction pathways important for tumor cell growth and survival, cell-cycle control, transcriptional regulation, and the modulation of cellular stress responses to endogenous and exogenous stimuli. The sensitivity of transformed cells to proteasome inhibitors and the successful design of treatment protocols with tolerable, albeit narrow, therapeutic indices have made proteasome inhibition a viable strategy for cancer treatment. Clinical validation of the proteasome as a molecular target was achieved with the approval of bortezomib, a boronic acid proteasome inhibitor, for the treatment of multiple myeloma and mantle cell lymphoma. Several "next-generation" proteasome inhibitors (carfilzomib and PR-047, NPI-0052, and CEP-18770) representing distinct structural classes (peptidyl epoxyketones, beta-lactones, and peptidyl boronic acids, respectively), mechanisms of action, pharmacological and pharmacodynamic activity profiles, and therapeutic indices have now entered clinical development. These agents may expand the clinical utility of proteasome inhibitors for the treatment of solid tumors and for specific non-oncological, i.e., inflammatory disease, indications as well. This chapter addresses the biology of the proteasome, the medicinal chemistry and mechanisms of action of proteasome inhibitors currently in clinical development, the preclinical and clinical pharmacological and safety profiles of bortezomib and the newer compounds against hematological and solid tumors. Future directions for research and other applications for this novel class of therapeutics agents are considered in this chapter.