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首页> 外文期刊>Chemistry & biology >Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib
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Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib

机译：蛋白酶体类胰蛋白酶样位点的特定细胞可渗透抑制剂选择性地使骨髓瘤细胞对硼替佐米和卡非佐米敏感

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摘要

Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological functions, and are established targets of anticancer drugs. The proteasome has three types of active sites. Chymotrypsin-like sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic drugs; however, our recent work demonstrated that inhibitors of caspase-like sites sensitize malignant cells to inhibitors of the chymotrypsin-like sites. Here, we describe the development of specific cell-permeable inhibitors and an activity-based probe of the trypsin-like sites. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites, including antimyeloma agents bortezomib and carfilzomib. Thus, trypsin-like sites are cotargets for anticancers drugs. Together with inhibitors of chymotrypsin- and caspase-like sites developed earlier, we provide the scientific community with a complete set of tools to separately modulate proteasome active sites in living cells.
机译：蛋白酶体降解哺乳动物细胞中的大多数蛋白质，参与多种生理功能的调节，并且是抗癌药物的既定目标。蛋白酶体具有三种类型的活性位点。胰凝乳蛋白酶样位点对于蛋白质分解最重要，长期以来一直被认为是抗肿瘤药的唯一合适靶点。然而，我们最近的工作表明，胱天蛋白酶样位点的抑制剂使恶性细胞对胰凝乳蛋白酶样位点的抑制剂敏感。在这里，我们描述了特定的细胞渗透性抑制剂和胰蛋白酶样部位的基于活性的探针的发展。这些化合物选择性地使多个骨髓瘤细胞对胰凝乳蛋白酶样位点的抑制剂敏感，包括抗骨髓瘤药物硼替佐米和卡非佐米。因此，胰蛋白酶样位点是抗癌药的共同靶标。连同较早开发的胰凝乳蛋白酶和半胱氨酸蛋白酶样位点的抑制剂，我们为科学界提供了一套完整的工具，可分别调节活细胞中的蛋白酶体活性位点。

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