The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

蛋白酶体是维持蛋白质稳态的重要细胞机器，在多发性骨髓瘤和可能的其他癌症中尤为重要。用硼替佐米和卡非佐米靶向蛋白酶体20S肽酶活性已广泛用于治疗骨髓瘤。但是，并非所有患者都对这些化合物有反应，而最终确有复发的患者。因此，迫切且未满足的需求来开发通过不同机制靶向蛋白变性的新药。我们确定喹啉-8-硫醇（8TQ）是蛋白酶体19S亚基Rpn11的一流抑制剂。8TQ的衍生物capzimin对Rpn11的选择性是相关JAMM蛋白酶的> 5倍，对其他几种金属酶的选择性是> 2 log。辣椒素稳定了蛋白酶体的底物，诱导了未折叠的蛋白质反应，并阻止了癌细胞的增殖，包括对硼替佐米耐药的癌细胞。蛋白质组学分析表明，辣椒素能稳定多泛素化底物的一部分。辣椒素的鉴定为开发用于癌症治疗的蛋白酶体抑制剂提供了另一种途径。