Enzymologie Moléculaire et Fonctionnelle, UR4, University Paris 6, Pierre et Marie Curie, UPMC-Sorbonne Universités, Case 256, 7 Quai Saint Bernard, 75252 Paris Cedex 05, France.
J Med Chem. 2013 Apr 25;56(8):3367-78. doi: 10.1021/jm4002007. Epub 2013 Apr 17.
Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously two of the six active sites of the eukaryotic 20S proteasome. The homodimerized compounds actively inhibited chymotrypsin-like (Ki = 6-11 nM) and trypsin-like activities, whereas postacid activity was poorly modified. The noncovalent binding mode was ascertained by X-ray crystallography of the inhibitors complexed with the yeast 20S proteasome. The inhibition of proteasomal activities in human cells was evaluated. The use of the multivalency inhibitor concept has produced highly efficient and selective noncovalent compounds (no inhibition of calpain and cathepsin) that have potential therapeutic advantages compared to covalent binders such as bortezomib and carfilzomib.
非共价蛋白酶体抑制剂引入了一种与癌症治疗中使用的共价抑制剂不同的抑制机制。本研究从 TMC-95A 的非共价线性模拟物出发，设计并优化了一系列使用聚氨基酸己酸间隔物的二聚化抑制剂，以同时靶向真核 20S 蛋白酶体的六个活性位点中的两个。同型二聚化合物积极抑制糜蛋白酶样（Ki = 6-11 nM）和胰蛋白酶样活性，而对后酸活性的修饰较差。通过与酵母 20S 蛋白酶体复合物的抑制剂的 X 射线晶体学确定了非共价结合模式。评估了抑制剂对人细胞中蛋白酶体活性的抑制作用。使用多价抑制剂概念产生了高效和选择性的非共价化合物（对钙蛋白酶和组织蛋白酶没有抑制作用），与硼替佐米和卡非佐米等共价结合物相比，具有潜在的治疗优势。
