Perez Christian, Li Jing, Parlati Francesco, Rouffet Matthieu, Ma Yuyong, Mackinnon Andrew L, Chou Tsui-Fen, Deshaies Raymond J, Cohen Seth M
Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
J Med Chem. 2017 Feb 23;60(4):1343-1361. doi: 10.1021/acs.jmedchem.6b01379. Epub 2017 Feb 13.
The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation. A fragment-based drug discovery (FBDD) approach was utilized to identify fragments with activity against Rpn11. Screening of a library of metal-binding pharmacophores (MBPs) revealed that 8-thioquinoline (8TQ, IC value ∼2.5 μM) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQ yielded a small molecule compound (35, IC value ∼400 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in culture.
蛋白酶体在降解那些碰巧组成型或诱导型不稳定的正常蛋白质过程中发挥着关键作用，并以此发挥调节作用。此外，它还能降解异常/受损/突变/错误折叠的蛋白质，起到质量控制功能。蛋白酶体抑制剂已在多发性骨髓瘤治疗中得到验证，有几种已获美国食品药品监督管理局批准的治疗药物。Rpn11是一种锌依赖性金属异肽酶，可从被转运至蛋白酶体进行降解的标记蛋白质上水解泛素。基于片段的药物发现（FBDD）方法被用于鉴定对Rpn11有活性的片段。对金属结合药效团（MBP）文库的筛选显示，8-硫代喹啉（8TQ，IC值约为2.5 μM）对Rpn11有强烈抑制作用。对8TQ的进一步合成修饰产生了一种小分子化合物（35，IC值约为400 nM），它是一种强效且选择性的Rpn11抑制剂，可阻断培养中的肿瘤细胞增殖。
