Chimie et photonique moléculaires, Université de Rennes 1, CNRS UMR 6510, bâtiment 10A, case 1012, Campus de Beaulieu, 35042 RENNES CEDEX, France.
Curr Top Med Chem. 2010;10(3):232-56. doi: 10.2174/156802610790725515.
The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side-effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases.
寻找蛋白酶体抑制剂的工作始于十五年前。这些抑制剂已被证明是研究受泛素-蛋白酶体途径调控的许多重要细胞过程的有力工具。靶向蛋白酶体途径还可能为癌症、肌肉萎缩症、炎症和自身免疫性疾病等疾病带来新的治疗方法。对于癌症来说，这已经成为现实；2003 年，FDA 批准了硼替佐米（一种有效的蛋白酶体抑制剂）用于治疗多发性骨髓瘤，2006 年用于治疗套细胞淋巴瘤。在一些早期蛋白酶体抑制剂中确定的化学结构导致了新的抗癌药物（CEP-18770、卡非佐米、NPI-0052）的开发。所有这些分子都是共价键抑制剂，与三种活性位点的催化 Thr1-O(gamma)反应。本综述涵盖了天然和合成蛋白酶体抑制剂的药物化学的最新进展。将重点介绍没有反应基团的非共价抑制剂的进展，因为它们应最大限度地减少副作用。最近已经确定了新的结构和新的作用模式，为治疗一系列疾病的新药候选物开辟了道路。
